Amidine compound, process for producing same and anti-complement agent comprising same

ABSTRACT

Amidino compounds represented by the formula (I) ##STR1## and pharmaceutically acceptable acid addition salts thereof are novel compounds and are useful as powerful antitrypsine, antiplasmin, antikallikrein and anti-thrombin agents. Having strong anti-Cl (Clr, Cls) activities and an anticomplement activity, they are also useful as anticomplement agents. These amidino compounds are prepared by usual esterification of carboxylic acid compounds represented by the formula (II) 
     
         R.sub.1 --COOH                                             (II) 
    
     with amidinophenol compound (III) and, if necessary, can be transformed into pharmaceutically acceptable acid addition salts thereof. ##STR2##

This is a continuation of Ser. No. 350,963, filed Feb. 22, 1982,abandoned.

This invention relates to novel amidino compounds (I) of the formula##STR3## having strong anti-trypsin, anti-plasmin, anti-kallikrein andanti-thrombin activities and also an anti-complement activity, and to aprocess for producing said novel compounds.

The present compound (I) has anti-trypsin, anti-plasmin, anti-thrombinand anti-complement activities stronger than those of leupeptin. Thismeans that with respect to anti-trypsin, anti-plasmin, anti-kallikrein,anti-thrombin and anti-complement activities, the same pharmaceuticaleffect is obtained with a smaller dose of the compound (I) than with adose of leupeptin.

An object of this invention is to provide a pharmaceutically usefulnovel amidino compounds represented by the formula (I) ##STR4## andpharmaceutically acceptable acid addition salts thereof.

Another object of this invention is to provide powerful anti-trypsin,anti-plasmin, anti-kallikrein and anti-thrombin agents.

A still another object of this invention is to provide powerfulanti-complement agents.

A further object of this invention is to provide a process for producingsaid novel amidino compounds.

The present compound (I) can be produced by subjecting a carboxylic acidcompound represented by the following formula (II) or a reactiveintermediate thereof and amidino phenol compound of the followingformula (III) to usual esterification: ##STR5##

This invention relates to an amidino compound represented by the formula(I) ##STR6##

In formulas of the amidino compound (I), the carboxylic acid compound(II) and the amidino phenol compound (III) described in thisspecification and the appended claims, R₁ represents a straight orbranched chain alkyl group of 1 to 6 carbon atoms, a straight orbranched chain alkenyl group of 2 to 6 carbon atoms including 1 to 3double bonds, R₃ --(CH₂)_(a) --, R₄ --(CH₂)_(b) --, ##STR7## where R₃ iscycloalkyl group of 3 to 6 carbon atoms or cycloalkenyl group of 3 to 6carbon atoms including 1 to 2 double bonds; a is 0, 1, 2 or 3; R₄ isamino or guanidino group possessing radical protecting group or not; bis a number of 1 to 5; R₅ and R₆, which may be the same or different,are each a hydrogen atom, straight or branched alkyl group of 1 to 4carbon atoms, --OR₇, methylenedioxy group, --SR₇, --COOR₇, --COR₈,--OCOR₉, --NHCOR₉, ##STR8## NO₂, CN, halogen atom, --CF₃ or ##STR9## R₇is hydrogen atom, straight or branched alkyl group of 1 to 4 carbonatoms or benzyl group; R₈ is hydrogen atom, straight or branched alkylgroup of 1 to 4 carbon atoms; R₉ is straight or branched alkyl group of1 to 4 carbon atoms; R₁₀ and R₁₁, which may be the same or different,are each a hydrogen atom, straight or branched alkyl group of 1 to 4carbon atoms, or amino radical protecting group; R₁₂ is O, S, or NH; R₁₃is 2',3'-dimethyl or 3'--CF₃ group; Z is --(CH₂)_(d) -- (d is 0, 1, 2 or3), ##STR10## R₁₄ is straight or branched alkyl group of 1 to 4 carbonatoms; R₁₅ is hydrogen atom, straight or branched alkyl group of 1 to 4carbon atoms; R₂ represents --R₁₆, --OR₁₆, --COOR₁₇, halogen atom,--NO₂, --SO₃ H, ##STR11## wherein R₁₆ is straight or branched alkylgroup of 1 to 4 carbon atoms; R₁₇ is hydrogen atom, straight or branchedalkyl group of 1 to 4 carbon atoms; R₁₈ is hydrogen atom or guanidinogroup.

In substituents R₁ -R₁₄, straight or branched alkyl group of 1 to 4carbon atoms include CH₃, C₂ H₅, n--C₃ H₇, i--C₃ H₇, n--C₄ H₉, i--C₄ H₉,sec--C₄ H₉, or t--C₄ H₉, and examples of straight or branched alkylgroup of 1 to 6 carbon atoms is CH₃, C₂ H₅, n--C₃ H₇, i--C₃ H₇, n--C₄H₉, i--C₄ H₉, sec--C₄ H₉, t--C₄ H₉, n--C₅ H₁₁, or n--C₆ H₁₃.

Straight or branched alkenyl group of 2 to 6 carbon atoms containing 1to 3 double bonds include ##STR12## as examples.

Cycloalkyl group of 3 to 6 carbon atoms or cycloalkenyl group of 3 to 6carbon atoms containing 1 to 2 double bonds include ##STR13## asexamples.

Amino or guanidino radical protecting group include t-butoxycarbonyl,benzyloxycarbonyl, acetyl, benzoyl, tosyl or nitro as examples.

Then, R₁ represents following examples: ##STR14##

Amidinophenol moiety in amidino compound (I) or amidino phenol compound(III) include ##STR15##

The compound (I) of this invention can be produced by the reactionbetween a carboxylic acid compound of the formula (II) or a reactiveintermediate thereof and an amidinophenol compound of the formula (III)or preferably an acid addition salt thereof. The reactive intermediates,as herein referred to, include acid halides and acid anhydrides commonlyused in the dehydration condensation and the reactive intermediatesformed by reacting dicyclohexyl carbodiimide (DCC),diphenylphosphorylazide (DPPA), or the like with a carboxylic acidderivative.

The process for producing the present compound is described below indetail.

The present compound (I) can be prepared by dissolving or suspending acarboxylic acid compound (II) in an organic solvent such asdimethylformamide, pyridine, or the like, then allowing the compound(II) to react with an carboxylic acid activator such asdicyclohexylcarbodiimide (DCC), diphenylphosphoryl azide (DPPA), or thelike, which is usually used as dehydration-condensation agent, andadding an amidinophenol compound (III) or preferably an acid additionsalt thereof to the reaction product.

For instance, when DCC is used as the dehydration-condensation agent, acarboxylic acid derivative (II) is added to a solvent such as pyridine,then the mixture is stirred with cooling in ice or at room temperaturefor 10 minutes to 2 hours, then acid addition salt of amidine phenolcompound (III) is added, and the mixture is further stirred at atemperature between -30° and 80° C., preferably at room temperature, for3 to 5 hours to complete the reaction, though it is not objectionable tocontinue the reaction overnight. Dicyclohexylurea (DCU) precipitates outof the reaction mixture, while the present compound (I) eitherprecipitates with DCU or remains dissolved in the solvent. In the formercase, both precipitates are collected by filtration, then suspended in asuitable solvent such as dimethylformamide or the like and the mixtureis filtered to remove insoluble DCU. After adding to the filtrate asolvent such as ethyl ether, ethyl acetate, acetone or the like, theprecipitate is collected by filtration to obtain the present compound(I). Alternatively, the combined precipitate of DCU and the presentcompound (I) is collected by filtration, then added to a suitablesolvent such as dimethylformamide, water or the like to remove insolubleDCU by filtration, the filtrate is added to a saturated aqueous sodiumbicarbonate solution to obtain the present compound (I) in the form ofcarbonate. In the latter case, where the present compound remainsdissolved in the reaction mixture, DCU is removed by filtration and thefiltrate is admixed with a solvent such as ethyl ether, acetone, ethylacetate, or the like to obtain the present compound (I).

In another process, when it is intended to use an acid halide as areactive intermediate of a carboxylic acid derivative (II), the latterderivative (II) is allowed to react with an acidhalogenation agent suchas SOCl₂, SOBr₂, PCl₅ or the like to synthesize an acid haliderepresented by the formula (IV)

    R.sub.1 --COX                                              (IV)

wherein R₁ is as defined above and X represents a halogen atom. The acidhalide is added to a solution of an amidinophenol compound (III),preferably in the form of an acid addition salt, dissolved indimethylformamide, pyridine, dimethyl sulfoxide or the like and allowsto react in the presence of a dehydrohalogenation agent. Thedehydrohalogenation agents which can be used include inorganic basessuch as potassium carbonate, sodium carbonate, sodium hydroxide and thelike and organic bases such as triethylamine, pyridine, dimethylanilineand the like. Of these bases, pyridine is preferred. Although thereaction proceeds readily at a temperature in the range of -30° to 80°C., it is preferable for the purpose of avoiding side reactions toconduct the reaction in the early stage under ice cooling and then atroom temperature. The reaction is complete in 2 to 5 hours, though thereaction mixture can be left overnight.

The present compound (I) can be also prepared by which an acid halide(IV) and an amidinophenol compound are mixed, small amount of CH₃ SO₃ Hor H₂ SO₄ is added therein and the mixture is warmed. After completionof the reaction, the reaction mixture is treated in a customary manner.For instance, when pyridine was used as the reaction medium, a solventsuch as ethyl ether or ethyl acetate is added to the reaction mixture toprecipitate a solid reaction product which is then recrystallized from asuitable solvent such as a methanol-ethyl ether mixture to obtain thepresent compound (I).

Further, if desired, the present compound (I) can be prepared in thecorresponding reduced form by the reduction of a suitable compound offormula (I) by use of a suitable reducing agent. For example, a compoundof formula (I) having a nitro group is converted into a compound offormula (I) having an amino group by the reduction. It is also possibleto convert a cinnamic acid ester derivative having a double bond into aphenylpropionic acid derivative.

Still further, if desired, the present compound can be obtained by theremoval of protective groups of amino, hydroxyl, and carboxyl groups.The protective groups, as herein referred to, include those which arecommonly used, such as, for example, benzyloxycarbonyl,tert-butoxycarbonyl, benzyl and tert-butyl groups. For instance, acompound having an aminomethyl group is obtained by the removal of theprotective group from a compound having a benzyloxycarbonylaminomethylgroup and a compound having a hydroxyl group is obtained from a compoundhaving a benzyloxy group.

If necessary, acid addition salts of the present compound may beprepared in a customary manner. For instance, carbonate of the presentcompound is dissolved or suspended in a solvent such as methanol, DMF orthe like and the carbonate is allowed to dissolve by the addition of anacid such as methanesulfonic acid, hydrochloric acid or the like. To theresulting solution is added a solvent such as ethyl ether, ethyl acetateor the like to obtain a corresponding acid addition salt. Acids whichcan be used are pharmaceutically acceptable ones including inorganicacids such as hydrochloric acid, sulfuric acid and phosphoric acid andorganic acids such as acetic acid, lactic acid, citric acid,methanesulfonic acid, succinic acid, fumaric acid and maleic acid.

Amidinophenol compound (III) is useful intermediate for preparation ofthe present compound (I). The amidinophenol compound (III) is preparedby various manner.

One is the method by introduction of substituent to amidinophenol (V),that is, introduction of NO₂ by HNO₃ /H₂ SO₄ (R₂ =2--NO₂), of SO₃ H byf--H₂ SO₄ (R₂ =2--SO₃ H), or of Br by BR₂ (R₂ =2, 6--diBr) toamidinophenol (V) is one of examples. ##STR16##

Another method is that nitril (VI) or amide (VII) of phenol is changedto iminoether (VIII) and then treated with ammonia to obtainamidinophenol compound (III) wherein A represent CH₃ or C₂ H₅, B and Xrepresent O or S. R₂ =3--CH₃, 2--OCH₃, 2--COOH, 2--COOCH₃, --2--Cl, or##STR17## is example by the above mentioned method. ##STR18##

The present compound and the pharmaceutically acceptable acid additionsalt thereof possess powerful inhibitory activities against proteases,that is, trypsin, plasmin, kallikrein and thrombin and are effective asan anti-trypsin agent for the treatment of pancreatitis, as ananti-plasmin or anti-kallikrein agent for hemorrhagic diseases, and asan anti-thrombin agent for thrombus.

With respect to the above-mentioned proteases, their roles in a livingbody, the relationship to the diseases, the clinical significance ofthese protease inhibitors and the significance of the tests hereinperformed are explained below:

I. Trypsin:

Trypsin is a protease existing originally in the form of proenzymetrypsinogen in the pancreas and the proenzyme is secreted into the smallintestine where it is transformed into trypsin by activation withenterokinase existing therein. Trypsin has a role as one of digestiveenzymes. If the trypsinogen is activated by any chance in the pancreasto form trypsin, the pancreas tissue will be injured to manifestclinically the symptoms of pancreatitis. In fact, it is known that in anexperiment using rat as test animal, when trypsin is injected converselyinto the pancreas, the onset of intense pancreatitis is observed but thedisease is cured by the administration of a trypsin inhibitor. From thisfact, it is presumable that the present compound having a strong trypsininhibitory activity is useful as an anti-trypsin agent which isclinically effective for the treatment of pancreatitis.

II. Plasmin:

Plasmin is an enzyme existing in the blood, usually in the form ofproenzyme plasminogen which is converted to plasmin by the activationwith a plasminogen tissue activator such as urokinase. This enzyme actsreversely to the action of thrombin, that is, it acts to dissolvefibrin. For this reason, plasmin plays an important role in securingblood flow through capillaries. However, when this enzyme becomesabnormally activated for some reason, it causes hemorrhagic diseases.This enzyme participates also in inflammation, increasing the vascularpermeability and causing edema or the like. Therefore, an inhibitor forthis enzyme is useful as a drug to treat hemorrhagic diseases andinflammation.

III. Kallikrein:

Kallikrein is an enzyme widely distributed in blood and other organs andglands, usually in the form of its precursor prekallikrein which isactivated with Hageman factor or other proteases. This enzymeparticipates in the hypotensive kallikrein-kinin system whichcounteracts the hyper tensive reninangiotensin system and plays animportant role in the control of blood pressure. This enzyme particpatesalso in exogenous coagulation system. Further, kallikrein originatedfrom organs or glands plays an important role in the improvement oflocal circulation. However, an abnormal activation, particularly anabnormal local activation, of this enzyme causes an insufficiency oflocal circulation due to the exaggeration of coagulation system, causinginflammation, ulcer, or the like. Therefore, a kallikrein inhibitor isuseful for the control of blood pressure and as a drug for the treatmentof inflammation or ulcer.

IV. Thrombin:

Thrombin is known as an enzyme having a blood coagulating activity. Innormal state, thrombin is formed by the activation of prothrombin in theblood when the vascular wall is injured. Thrombin acts to decompose thefibrinogen in the blood into fibrin. The resulting fibrin deposits onthe injured part of vascular wall to prevent plasma components fromtransudation and simultaneously to promote the restoration of tissues.However, when the coagulation system is abnormally activated for somereason, a large number of fine thrombus are formed in capillariesthroughout the entire body. Therefore, the present compound is useful asa drug for the treatment of such a disease.

The present compound and its pharmaceutically acceptable acid additionsalts possess a strong C1 esterase (C1r, C1s) inhibitory activity, anability of inhibiting the complement mediated hemolysis, and atherapeutic activity against the Masugi Nephritis in which theactivation of the complement system caused by an immune complex is saidto play an important role. This indicates that the present compound isuseful as an anti-complement agent effective for the treatment ofallergic diseases such as nephritis associated with the complement.

The role of complement in the living body, the interrelation between adisease and the complement, the clinical significance of inhibitor, andthe significance of tests (inhibition of C1r, C1s, complement mediatedhemolysis, and Masugi nephritis) performed by the present inventors aredescribed below.

Anti-complement activity:

(1) C1r, C1s:

The complement is one of the serum components and comprises 9 componentsof C1 to C9. C1 is separated into 3 subcomponents of C1q, C1r and C1s.C1s and C1r means activated C1s and activated C1r, respectively. Thecomplenent was though at as first to perform a part of the infectionprotective process of living body, since it shows bacteriolysis, butrecently an intimate relation to the immunity has been evident. It wasshown that the complement is activated by the immune complexprogressively from C1 to C9 and exhibits cytolysis of hemolysis at thefinal stage (activation of C9). It was also disclosed that the fragments(e.g. C3a, C5a) liberated in the course of activation of the complementsystem exaggerate the vascular permeability and promote the chemotaxisof polymorphonuclear leucocytes or immune adherence. Since that time,the interrelationship between the abnormal activation of complement andvarious diseases, particularly immune diseases, has been extensivelyinvestigated and, as the result, the intimate association of autoimmunediseases with the complement is beginning to be disclosed. Examples ofautoimmune diseases caused by the abnormal activation of complementinclude autoimmune hemolytic anemia, autoimmune thrombocytopenia,leukopenia, glomerulonephritis, systemic lupus erythematosus, serumsickness and periarteritis nodosa. It is expectable to cure suchdiseases by inhibiting the activation of complement or inhibiting theactivated complement in an early stage. The present inventors examinedthe C1 esterase inhibitory effect of the present compound by using C1esterase as target enzyme and, in addition, the influence of the presentcompound on the complement system to estimate the usefulness of thepresent compound as a drug for the treatment of autoimmune diseases.

(2) Complement mediated hemolysis:

The complement mediated hemolysis is widely used as a means to determinethe titration of complement. The principle of this method is based onthe fact that hemolysis is caused by the activation of complement, whenthe latter is added to a complex (immune complex) of erythrocytes andthe antibody thereof. The degree of hemolysis varies in proportion tothe amount of complement added. Therefore, when a known amount ofcomplement admixed with a C1 esterase inhibitor is used, the hemolysismust be suppressed in proportion to the inhibitory activity. The presentcompound having C1 esterase inhibitory activity showed strong inhibitionof complement mediated hemolysis as shown hereinafter.

(3) Masugi's nephritis

Masugi nephritis is known to be an experimental nephritic model closelyresembling the human glomerulonephritis. This nephritic model may beinduced in rats by injection of heterologus anti-rat-kidney serum. Forthe onset of Masugi's nephritis, an important role is played by theactivation of complement system induced by the antigen-antibodyreaction. It is, therefore, expectable that a compound having aC1-esterase inhibitory activity will improve the progress of Masuginephritis.

The protein content of the animal's urine is used as the parameter forthe progress of Masugi nephritis. As shown in Table 3, Compound No. 69of the present invention distinctly decreased the protein content ofurine. From the result, it may be said that the compound of thisinvention having a C1-esterase inhibitory activity is useful as a remedyfor the glomerulonephritis and is also useful as a remedy for autoimmunediseases inclusive of glomerulonephritis.

Anti-trypsin, anti-plasmin, anti-kallikrein and anti-thrombin activities

The anti-trypsin, anti-plasmin, anti-kallikrein and anti-thrombinactivities were determined according to the method of Muramatsu et al.[M. Muramatsu, T. Onishi, S. Makino, Y. Hayashi and S. Fujii, J. ofBiochem., 58, 214 (1965)]. The results were as shown in Table 1. Thedata summarized in Table 1 are expressed in terms of molar concentration(ID₅₀) of the test compound which inhibits 50% of the activity of eachenzyme to hydrolyze TAME (tosylarginine methyl ester). The compound No.corresponds to the compound number shown in Examples.

                  TABLE 1                                                         ______________________________________                                        Compound                                                                      No.       Trypsin   Plasmin  Kallikrein                                                                            Thrombin                                 ______________________________________                                        1         >10.sup.-5                                                                              >10.sup.-5                                                                             >10.sup.-5                                                                            >10.sup.-5                               2         >10.sup.-5                                                                              >10.sup.-5                                                                             >10.sup.-5                                                                            >10.sup.-5                               4                                                                             5         7 × 10.sup.-7                                                                     3 × 10.sup.-7                                                                    1 × 10.sup.-6                                                                   2 × 10.sup.-6                      6         2 × 10.sup.-7                                                                     4 × 10.sup.-7                                                                    3 × 10.sup.-7                                                                   8 × 10.sup.-8                      7         >10.sup.-5                                                                              4 × 10.sup.-6                                                                    >10.sup.-5                                                                            5 × 10.sup.-7                      8         2 × 10.sup.-6                                                                     2 × 10.sup.-6                                                                    3 × 10.sup.-6                                                                   1 × 10.sup.-7                      9                                                                             10        >10.sup.-5                                                                              >10.sup.-5                                                                             >10.sup.-5                                                                            2 × 10.sup.-6                      11        >10.sup.-5                                                                              >10.sup.-5                                                                             >10.sup.-5                                                                            >10.sup.-5                               12        6 × 10.sup.-6                                                                     >10.sup.-5                                                                             >10.sup.-5                                                                            4 × 10.sup.-6                      13        >10.sup.-5                                                                              >10.sup.-5                                                                             >10.sup.-5                                                                            >10.sup.-5                               14        10.sup.-5 10.sup.-5                                                                              10.sup.-5                                                                             10.sup.-5                                15                                                                            16        1 × 10.sup.-5                                                                     3 × 10.sup.-7                                                                    5 × 10.sup.-6                                                                   1 × 10.sup.-6                      17        >10.sup.-5                                                                              >10.sup.-5                                                                             >10.sup.-5                                                                            >10.sup.-5                               18        3 × 10.sup.-5                                                                     5 × 10.sup.-7                                                                    1 × 10.sup.-6                                                                   4 × 10.sup.-6                      19        >10.sup.-5                                                                              >10.sup.-5                                                                             >10.sup.-5                                                                            >10.sup.-5                               20        1 × 10.sup.-6                                                                     6 × 10.sup.-7                                                                    6 × 10.sup.-7                                                                   5 × 10.sup.-7                      21        >10.sup.-5                                                                              >10.sup.-5                                                                             >10.sup.-5                                                                            >10.sup.-5                               22        >10.sup.-5                                                                              >10.sup.-5                                                                             >10.sup.-5                                                                            2 × 10.sup.-6                      23        1 × 10.sup.-5                                                                     2 ×   10.sup.-5                                                                  6 × 10.sup.-5                                                                   2 × 10.sup.-7                      24        3 × 10.sup.-6                                                                     >10.sup.-5                                                                             >10.sup.-5                                                                            4 × 10.sup.-6                      25        3 × 10.sup.-7                                                                     6 × 10.sup.-7                                                                    >10.sup.-5                                                                            1 × 10.sup.-7                      26        4 × 10.sup.-7                                                                     4 × 10.sup.-7                                                                    2 × 10.sup.-6                                                                   6 × 10.sup.-8                      27        3 × 10.sup.-7                                                                     4 × 10.sup.-7                                                                    4 × 10.sup.-6                                                                   1 × 10.sup.-7                      28        1 × 10.sup.-5                                                                     7 × 10.sup.-6                                                                    >10.sup.-5                                                                            3 × 10.sup.-6                      29        8 × 10.sup.-7                                                                     4 × 10.sup.-7                                                                    1 × 10.sup.-6                                                                   3 × 10.sup.-8                      30        3 × 10.sup.-7                                                                     4 × 10.sup.-7                                                                    2 × 10.sup.-7                                                                   3 × 10.sup.-8                      31        8 × 10.sup.-6                                                                     3 × 10.sup.-6                                                                    4 × 10.sup. -5                                                                  2 × 10.sup.-5                      32                                                                            33        >10.sup.-5                                                                              >10.sup.-5                                                                             >10.sup.-5                                                                            >10.sup.-5                               34        4 × 10.sup.-6                                                                     4 × 10.sup.-6                                                                    >10.sup.-5                                                                            3 × 10.sup.-6                      35        1 × 10.sup.-6                                                                     5 × 10.sup.-6                                                                    >10.sup.-5                                                                            3 × 10.sup.-6                      36                                                                            37        5 × 10.sup.-8                                                                     4 × 10.sup.-7                                                                    7 × 10.sup.-7                                                                   3 × 10.sup.-7                      38        2 × 10.sup.-8                                                                     4 × 10.sup.-7                                                                    1 × 10.sup.-6                                                                   2 × 10.sup.-7                      39        1 × 10.sup.-8                                                                     2 × 10.sup.-7                                                                    4 × 10.sup.-7                                                                   2 × 10.sup.-7                      40                                                                            41                                                                            42        7 × 10.sup.-8                                                                     3 × 10.sup.-7                                                                    3 × 10.sup.-7                                                                   7 × 10.sup.-8                      43                                                                            44        2 × 10.sup.-8                                                                     3 × 10.sup.-6                                                                    3 × 10.sup.-7                                                                   2 × 10.sup.- 6                     45        2 × 10.sup.-8                                                                     3 × 10.sup.-7                                                                    4 × 10.sup.-7                                                                   2 × 10.sup.-7                      46        5 × 10.sup.-8                                                                     6 × 10.sup.-7                                                                    3 × 10.sup.-7                                                                   4 × 10.sup.-8                      47        >10.sup.-5                                                                              >10.sup.-5                                                                             >10.sup.-5                                                                            >10.sup.-5                               48        2 × 10.sup.-6                                                                     2 × 10.sup.-7                                                                    8 × 10.sup.-6                                                                   4 × 10.sup.-7                      49        3 × 10.sup.-8                                                                     2 × 10.sup.-7                                                                    4 × 10.sup.-7                                                                   <10.sup.-8                               50        4 × 10.sup.-6                                                                     5 × 10.sup.-7                                                                    >10.sup.-5                                                                            2 × 10.sup.-7                      51        2 × 10.sup.-7                                                                     3 × 10.sup.-7                                                                    >10.sup.-5                                                                            9 × 10.sup.-7                      52        3 × 10.sup.-6                                                                     2 × 10.sup.-7                                                                    >10.sup.-5                                                                            9 × 10.sup.-8                      53                                                                            54        2 × 10.sup.-8                                                                     3 × 10.sup.-7                                                                    4 × 10.sup.-7                                                                   9 × 10.sup.-8                      55                                                                            56        5 × 10.sup.-8                                                                     3 × 10.sup.-7                                                                    4 × 10.sup.-7                                                                   6 × 10.sup.-8                      57        2 × 10.sup.-6                                                                     2 × 10.sup.-7                                                                    3 × 10.sup.-6                                                                   8 × 10.sup.-6                      58        8 × 10.sup.-6                                                                     8 × 10.sup.-6                                                                    2 × 10.sup.-6                                                                   >10.sup.-5                               59        5 × 10.sup.-7                                                                     7 × 10.sup.-8                                                                    7 × 10.sup.-7                                                                   4 × 10.sup.-6                      60        1 × 10.sup.-6                                                                     4 × 10.sup.-6                                                                    2 × 10.sup.-6                                                                   >10.sup.-5                               61        2 × 10.sup.-7                                                                     2 × 10.sup.-7                                                                    1 × 10.sup.-6                                                                   4 × 10.sup.-7                      62        5 × 10.sup.-7                                                                     3 × 10.sup.-6                                                                    2 × 10.sup.-6                                                                   5 × 10.sup.-4                      63                                                                            64                                                                            65                                                                            66        1 × 10.sup.-8                                                                     4 × 10.sup.-7                                                                    2 × 10.sup.-7                                                                   2 × 10.sup.-7                      67                                                                            68                                                                            69        8 × 10.sup.-8                                                                     2 × 10.sup.-6                                                                    4 × 10.sup.-7                                                                   2 × 10.sup.-7                      70        3 × 10.sup.-8                                                                     7 × 10.sup.-7                                                                    4 × 10.sup.-5                                                                   5 × 10.sup.-7                      71        4 × 10.sup.-8                                                                     2 × 10.sup.-6                                                                    3 × 10.sup.-5                                                                   2 × 10.sup.-6                      ______________________________________                                    

Anti-complement activity

(1) Anti-C1 (C1r, C1s) activity and inhibition of complement mediatedhemolysis:

The anti-C1 esterase (C1r, C1s) activity was determined according to themethod of Okamura et al. [K. Okamura, M. Muramatsu and B. Fujii,Biochem. Biophys. Acta, 295, 252-257 (1973)]. The inhibition ofcomplement mediated hemolysis was determined according to the method ofBaker et al. [B. R. Baker and E. H. Erickson, J. Med. Chem., 12, 408-414(1969)]. The results obtained were as shown in Table 2. The figures inTable 2 have the following meanings:

C1r: Molar concentration of the test compound which inhibits 50% of theability of C1r to hydrolyse AAME (acetylarginin methyl ester) (ID₅₀).

C1s: Molar concentration of the test compound which inhibits 50% of theability of C1s to hydrolyse ATEE (acetyltyrosin ethyl ester).

Inhibition of complement mediated hemolysis (%): The inhibitory activityis shown in terms of percent inhibition of the compound at variedconcentrations.

Compound No.: The compound number shown in Examples.

                  TABLE 2                                                         ______________________________________                                                            Inhibition of complement mediated                         Com-                hemolysis (%)                                             pound Anti-Cl activity            1 ×                                                                           1 ×                             No.   Cl-r     Cl-s     1 × 10.sup.-4                                                                  1 × 10.sup.-5                                                                   10.sup.-6                                                                           10.sup.-7                        ______________________________________                                        1     >10.sup.-5        95.9   37.3   16.0  0                                 2     NE                97.3   30.1   3.9   2.1                               3                       44.4   5.0    18.0  0                                 4                       95.0   67.2   8.7   0                                 5     5 × 10.sup.-6                                                                    9 × 10.sup.-7                                                                    100    97.0   47.2  3.0                               6     1 × 10.sup.-6                                                                    3 × 10.sup.-7                                                                    100    97.7   52.9  5.0                               7     >10.sup.-5        99.0   78.2   10.2  1.7                               8     >10.sup.-5        199.0  90.5   22.0  0                                 9                       171.6  16.2   2.5   0                                 10    >10.sup.-5        95.9   80.3   17.0  2.3                               11    >10.sup.-5        17.4   2.5    2.5   3.5                               12    >10.sup.-5                                                                             5 × 10.sup.-6                                                                    91.3   57.8   15.0  3.8                               13    >10.sup.- 5                                                                            >10.sup.-5                                                                             15.9   9.8    0     0                                 14    >10.sup.-5                                                                             >10.sup.-5                                                                             63.6   16.2   7.0   0                                 15                      98.8   81.7   12.7  0                                 16    >10.sup.-5                                                                             8 × 10.sup.-7                                                                    91.2   61.8   17.4  3.4                               17    >10.sup.-5                                                                             >10.sup.-5                                                                             98.6   78.2   20.4  0                                 18    >10.sup.-5                                                                             2 × 10.sup.-6                                                                    98.8   73.2   11.4  2.2                               19    >10.sup.-5                                                                             >10.sup.-5                                                                             99.2   83.4   15.0  5.0                               20    >10.sup.-5                                                                             3 × 10.sup.-7                                                                    96.8   80.3   13.0  1.8                               21    >10.sup.-5                                                                             4 × 10.sup.-6                                                                    99.3   99.9   60.2  10.9                              22    6 × 10.sup.-6                                                                    >10.sup.-5                                                                             22.8   0      0     0                                 23    7 × 10.sup.-6                                                                    5 × 10.sup.-6                                            24    >10.sup.-5                                                                             2 × 10.sup.-6                                                                    88.2   29.1   11.0  16.7                              25    4 × 10.sup.-6                                                                    2 × 10.sup.-7                                                                    100.0  93.1   38.6  11.6                              26    2 × 10.sup.-7                                                                    3 × 10.sup.-7                                                                    100.0  99.4   61.6  16.7                              27    5 × 10.sup.-7                                                                    2 × 10.sup.-7                                                                    100    100    95.5  26.2                              28    >10.sup.-5                                                                             3 × 10.sup.-6                                                                    79.1   25.0   22.8  23.8                              29    3 × 10.sup.-6                                                                    3 × 10.sup.-7                                                                    98.4   97.9   67.8  8.0                               30    9 × 10.sup.-7                                                                    3 × 10.sup.-7                                                                    100    100    99.0  45.3                              31    2 × 10.sup.-6                                                                    3 × 10.sup.-6                                                                    97.2   80.5   15.8  1.8                               32                      63.9   97.5   7.1   0                                 33    >10.sup.-5                                                                             >10.sup.-5                                                                             94.1   20.4   0     0                                 34    3 × 10.sup.-6                                                                    3 × 10.sup.-6                                                                    99.6   96.7   53.7  12.4                              35    4 × 10.sup.-7                                                                    3 × 10.sup.-7                                                                    88.8   43.9   29.9  11.8                              36                      100    100    100   90.4                              37    4 × 10.sup.-8                                                                    6 × 10.sup.-8                                                                    95.9   37.3   16.0  0                                 38    3 × 10.sup.-7                                                                    3 × 10.sup.-7                                                                    98.6   100    96.1  37.2                              39    4 × 10.sup.-7                                                                    2 × 10.sup.-7                                                                    0      95.4   96.8  52.1                              40                      87.5   68.1   7.8   2.0                               41                      66.7   9.3    0     0                                 42    1 × 10.sup.-6                                                                    4 × 10.sup.-8                                                                    100    99.1   70.0  7.6                               43                      95.0   50.4   3.7   0                                 44    4 × 10.sup.-6                                                                    6 × 10.sup.-7                                                                    99.1   94.1   29.0  29.2                              45    9 × 10.sup.-7                                                                    4 × 10.sup.-7                                                                    0      90.2   6.0   0                                 46    2 × 10.sup.-6                                                                    9 × 10.sup.-8                                                                    100    98.0   67.6  5.0                               47    >10.sup.-5                                                                             3 × 10.sup.-8                                                                    33.5   10.4   13.4  0                                 48    >10.sup.-5                                                                             3 × 10.sup.-6                                                                    94.0   94.8   75.3  23.2                              49    1 × 10.sup.-6                                                                             83.8   94.6   97.5  75.1                              50    9 × 10.sup.-6                                                                    >10.sup.-5                                                                             98.8   75.4   6.9   0                                 51    >10.sup.-5                                                                             3 × 10.sup.-6                                                                    99.1   90.9   15.0  0                                 52    5 × 10.sup.-6                                                                    3 × 10.sup.-6                                                                    100    98.8   75.4  12.8                              53                      87.5   25.2   --    3.5                               54    2 × 10.sup.-6                                                                    2 × 10.sup.-7                                                                    99.1   98.6   79.4  41.1                              55                      100    96.9   60.8  3.5                               56    1 ×  10.sup.-6                                                                   5 × 10.sup.-7                                                                    99.1   98.1   88.1  20.4                              57    >10.sup.-5                                                                             2 × 10.sup.-6                                                                    70.5   14.8   2.3   0                                 58    >10.sup.-5                                                                             4 × 10.sup.-6                                                                    93.4   20.0   3.0   0                                 59    2 × 10.sup.-6                                                                    3 × 10.sup.-7                                                                    100    100    76.0  15.6                              60    3 × 10.sup.-6                                                                    8 × 10.sup.-7                                                                    100    100    89.8  44.4                              61    4 × 10.sup.-7                                                                    3 × 10.sup.-7                                                                    98.6   100    98.0  76.1                              62    5 × 10.sup.-7                                                                    6 × 10.sup.-7                                                                    100    100    100   95.4                              63                      100    100    98.0  94.5                              64                      100    100    97.1  75.7                              65                      81.7   9.8    0     0                                 66    3 × 10.sup.-6                                                                    4 × 10.sup.-8                                                                    99.1   96.4   41.7  0                                 67                      99.2   99.2   96.9  57.5                              68                      100    92.9   50.6  5.8                               69    2 × 10.sup.-6                                                                    4 × 10.sup.-7                                                                    100    99.6   86.5  7.2                               70    3 × 10.sup.-6                                                                    2 × 10.sup.-7                                                                    100    100    97.0  46.1                              71    4 × 10.sup.-6                                                                    7 × 10.sup.-7                                                                    90.6   35.3   2.7   9.0                               72    1 × 10.sup.-6                                                                    2 × 10.sup.-7                                                                    100    87.8   10.8  0                                 73                      100    100    89.9  46.1                              74    >10.sup.-5                                                                             3 × 10.sup.-6                                                                    55.4   5.7    3.6   0                                 75    8 × 10.sup.-6                                                                    3 × 10.sup.-6                                                                    45.2   3.2    0     0                                 76    >10.sup.-5                                                                             >10.sup.-5                                                                             34.8   4.8    0     0                                 77    >10.sup.-5                                                                             8 × 10.sup.-7                                                                    97.3   48.9   1.8   0                                 78    >10.sup.-5        97.4   58.8   7.0   0                                 79    >10.sup.-5        95.1   96.8   81.7  48.1                              80    >10.sup.-5                                                                             >10.sup.-5                                                                             66.5   6.9    0     0                                 81    >10.sup.-5                                                                             >10.sup.-5                                                                             98.2   71.6   4.2   0                                 82    >10.sup.-5                                                                             >10.sup.-5                                                                             29.8   0      0     0                                 83    9 × 10.sup.-6                                                                    4 × 10.sup.-6                                                                    100    90.2   12.9  --                                84    >10.sup.-5                                                                             4 × 10.sup.-7                                                                    98.6   67.7   2.0   0                                 85    6 × 10.sup.-7                                                                    5 ×  10.sup.-7                                                                   98.6   97.9   67.1  7.0                               86                      100    97.1   53.6  11.0                              87    >10.sup.-5                                                                             5 × 10.sup.-6                                                                    0      0      0     0                                 Leu-  2 × 10.sup.-4                                                                    2 × 10.sup.-5                                                                    97     52     0     0                                 peptin                                                                        ______________________________________                                    

(3) Masugi nephritis:

Pharmacological test (Therapeutic experiment on Masugi's nephritis).

Experimental nephritis were induced in rats by intravenous injection ofnephrotoxin prepared according to the method of Shibata et al.["Experimental Immunoallergy.", p. 664 (1971), Bunkodo, Tokyo]. Eachmember of the medicine administered group had been orally administeredwith methanesulfonate of Compound No. 69 at a dose rate of 100 mg/kgbody weight, twice a day, for eight consecutive days. On the second dayfrom the beginning of medicine administration, nephrotoxin wasintravenously administered. The effectiveness was evaluated bydetermining the difference in protein content of urine between thenephritic group (control group) and the medicine administered group onthe 6th day (5th day after the administration of nephrotoxin) and 9thday from the beginning of medicine administration. The results obtainedwere as shown in Table 3.

                  TABLE 3                                                         ______________________________________                                                         5th day                                                                              8th day                                               ______________________________________                                        Percentage inhibition                                                                            81%      39%                                               ______________________________________                                    

The percentage inhibition indicates the degree of decrease in proteincontent of urine of the medicine administered group as compared with thecontrol group.

Method of administration:

The present compound is most suitably administered orally, though can beadministered by injection. It is used as a drug either alone or incombination with other drugs. It is administered generally in the formof medicinal composition, though can be administered as simple substancewithout any additive. Examples of medicinal compositions includetablets, powderes, capsules, syrups and solutions. An oral compositionmay contain common additives such as binders, diluents, lubricants,disintegrators and excipients. Oral solutions may be in the form ofaqueous or oily suspension, solution, emulsion, syrup or elixir, or inthe form of dry syrup which, before use, is readjusted with water orother suitable solvents. The solutions may contain common additives suchas suspending agents, flavoring agents, diluents, or emulsifies. Forinjection, may be used aqueous suspensions or oily suspensions.

Dosage:

The present compound may be administered to mammals (including man)orally at a dose of 10 to 20 mg per day or by intravenous injection at adose of 1 to 20 mg per day. However, these doses are presented solelyfor the sake of example. A suitable dose for a patient should bedetermined depending upon the age and body weight of the patient and thefeatures of illness.

Examples of pharmaceutical formulations are described below. Examples ofpharmaceutical formulations:

    ______________________________________                                        (1) Capsules.                                                                 The present compound     100.0  mg                                            Lactose                  59.0                                                 Crystalline cellulose    33.4                                                 Calcium carboxymethylcellulose                                                                         3.6                                                  Magnesium stearate       4.0                                                  Total                    200.0  mg                                            (2) Fine granules.                                                            The present compound     50.0   mg                                            Lactose                  249.0                                                Mannitol                 75.0                                                 Corn starch              110.0                                                Hydroxypropylcellulose   16.0                                                 Total                    500.0  mg                                            (3) Injections.                                                               The present compound     5.0    mg                                            Water for injection      2      ml                                            ______________________________________                                    

Made up to injections in a customary manner.

Toxicity:

The median lethal dose (LD₅₀) of the present compound is as shown inTable 4.

                  TABLE 4                                                         ______________________________________                                        Compound         LD.sub.50 mg/kg                                              No.              IP      PO                                                   ______________________________________                                        69               192     1,700                                                70               200     2,500                                                ______________________________________                                    

Examples of preparation of the present compounds are described below.The physical data of each compound are summarized in Table 5.

EXAMPLE 1 Synthesis of 4-amidino-2-benzoylphenyl acetate ##STR19##

Into 30 ml of dried pyridine, was dissolved 5.0 g of4-amidino-2-benzoylphenol methanesulfonate. To the solution, while beingcooled in ice and stirred, was added slowly a solution of 1.2 g ofacetyl chloride in 5 ml of dried DMF. After stirring at room temperaturefor one hour, the mixture was filtered to remove a precipitate and theprecipitate was washed with pyridine. Upon addition of ethyl ether anoily matter separated out of the filtrate. The oily matter was washed afew times with ethyl ether and dissolved in water. A saturated aqueoussodium hydrogen-carbonate solution was added to the resulting aqueoussolution to precipitate the carbonate of Compound No. 1. The carbonatewhich was collected by filtration was washed with water, then withacetone and dried to obtain 3.5 g of the anhydrous carbonate. Theanhydrous carbonate was suspended in 10 ml of methanol and admixed with1.2 g of methanesulfonic acid. The crystals disappeared by dissolution,but after a while colorless crystal precipitated again. After additionof ethyl ether, the crystals were collected by filtration, andrecrystallized from ethanol to obtain 2.5 g of colorless needle crystalsof 4-amidino-2-benzoylphenyl acetate methanesulfonate.

EXAMPLE 2 Synthesis of 4-amidino-2-nitrophenyl acetate ##STR20##

To a suspension of 3.0 g of 4-amidino-2-nitrophenol methanesulfonate in15 ml of acetic anhydride, was added 0.5 ml of methanesulfonic acid. Themixture was refluxed with stirring for 10 to 20 minutes. The crystalsdissolved slowly, forming a clear yellow solution. Upon standing at roomtemperature, colorless crystals separated out of the solution. Thecrystals were ashed with ethyl ether and recrystallized from ethanol toobtain 3.0 g of colorless needle crystals of 4-amidino-2-nitrophenylacetate methanesulfonate.

EXAMPLE 3 Synthesis of 4-amidino-2-methoxyphenyl isovalerate ##STR21##

Into 40 ml of anhydrous pyridine, was dissolved 1.5 g of isovalericacid. To the solution, while being cooled in ice, was added 3.7 g of DCCand the resulting mixture was stirred for 30 minutes. After addition of3.9 g of 4-amidino-2-methoxyphenol methanesulfonate, the mixture wasstirred overnight at room temperature. The precipitate which was formedwas separated by filtration and washed with pyridine. Ethyl ether wasadded to the filtrate to precipitate colorless crystals. The crystalswere washed with ethyl ether, dissolved in DMF, and recrystallized byadding ethyl ether. The crystals were further purified byrecrystallizing from an ethanol-ethyl ether mixture to obtain 3.4 g ofcolorless flaky crystals of 4-amidino-2-methoxyphenyl isovaleratemethanesulfonate.

EXAMPLE 4

The procedures similar to those of Examples 1 to 3 were followed toobtain the following compounds: ##STR22##

EXAMPLE 5 Synthesis of 4-amidino-2-nitrophenyl cyclopropanecarboxylate##STR23##

In 5.0 ml of cyclopropanecarboxyl chloride, was suspended 2.0 g of4-amidino-2-nitrophenol methanesulfonate. After addition of 2 drops ofmethanesulfonic acid, the suspension was heated with vigorous stirringin an oil bath at 80° C. The temperature of the oil bath was graduallyelevated to keep the suspension refluxing, whereby the crystalsgradually dissolved. The refluxing was continued for a while whensuddenly the whole mixture turned into a pale yellow solid mass. Thesolid mass was washed out of the vessel with ethyl ether andrecrystallized from ethanol to obtain 2.0 g of pale yellow granularcrystals of 4-amidino-2-nitrophenyl cyclopropanecarboxylatemethanesulfonate.

EXAMPLE 6

The following compounds were obtained in a manner similar to that inExample 1, 2, 3 or 5: ##STR24##

EXAMPLE 7 Synthesis of 4-amidino-2-benzoylphenyl3-benzyloxycarbonylaminopropionate ##STR25##

Into 50 ml of anhydrous pyridine, was dissolved 3.3 g of3-benzyloxycarbonylaminopropionic acid. To the solution, while beingcooled in ice, was added 3.7 g of DCC. The mixture was stirred for 30minutes. After addition of 5.0 g of 4-amidino-2-benzoylphenolmethanesulfonate, the mixture was further stirred overnight. Theprecipitate which was formed was separated by filtration and washed withpyridine. Ethyl ether was added to the filtrate to separate an oilysubstance which solidified upon stirring. The solidified substance wascollected by filtration, washed with ethyl ether, and dissolved in DMF.The crystals precipitated out of the DMF solution by the addition ofethyl ether were recrystallized from ethanol to yield 3.9 g of colorlessgranular crystals of 4-amidino-2-benzoylphenyl3-benzyloxycarbonylaminopropionate methanesulfonate.

EXAMPLE 8 Synthesis of 4-amidino-2-benzoylphenyl 3-aminopropionate##STR26##

To 4.0 ml of a 30% hydrogen bromide-acetic acid mixture, was added 1.0 gof 4-amidino-2-benzoylphenyl 3-benzyloxycarbonylaminopropionatemethanesulfonate. The mixture was stirred for one hour at roomtemperature to dissolve the crystals, forming a homogeneous yellowsolution. Anhydrous ethyl ether was added to the solution to precipitatea white or pale yellow powder. After removing the supernatant, theresidue was washed a few times with ethyl ether to obtain 0.5 g of ahydroscopic powder of 4-amidino-2-benzoylphenyl 3-aminopropionatedihydrobromide.

EXAMPLE 9 Synthesis of 4-amidino-2-benzoylphenyl6-benzoyloxycarbonylaminocaproate ##STR27##

Into 50 ml of anhydrous pyridine, was dissolved 4.0 g of6-benzyloxycarbonylaminocaproic acid. To the solution, while beingcooled in ice, was added 3.7 g of DCC. After having been stirred for 30minutes, the mixture was admixed with 5.0 g of 4-amidino-2-benzoylphenolmethanesulfonate and stirred overnight at room temperature. Theprecipitate which was formed was separated by filtration and washed withpyridine. Ethyl ether was added to the filtrate to precipitate whitecrystals. The crystals were collected by filtration, washed with ethylether, dissolved in DMF, and admixed with ethyl ether to precipitatecolorless crystals which were collected by filtration and dried toobtain 5.7 g of an anhydrous substance. This substance wasrecrystallized from ethanol to obtain 2.7 g of colorless needle crystalsof 4-amidino 2-benzoylphenyl 6-benzyloxycarbonylaminocaproatemethanesulfonate.

EXAMPLE 10 Synthesis of 4-amidino-2-benzoylphenyl 6-aminocaproate##STR28##

To 8.0 ml of a 30% hydrogen bromide-acetic acid mixture, was added 1.7 gof 4-amidino-2-benzoylphenyl 6-benzyloxycarbonylaminocaproatemethanesulfonate. The mixture was stirred for one hour at roomtemperature, whereby the crystals dissolved in 4 to 5 minutes, forming auniform solution. Upon addition of anhydrous ethyl ether to thesolution, an oily substance separated out. The supernatant was removedand the oily substance was washed a few times with ethyl ether. The oilysubstance was dissolved with heating in a small volume of water, admixedwith acetone, and stirred while cooling in ice, to obtain 0.9 g of acolorless powder of 4-amidino-2-benzoylphenyl 6-aminocaproatedihydrobromide.

EXAMPLE 11 Synthesis of 4-amidino-2-methoxyphenyl 6-guanidinocaproate##STR29##

To 40 ml of anhydrous pyridine, was added 2.1 g of 6-guanidinocaproicacid hydrochloride. To the mixture, while being cooled in ice, was added2.5 g of DCC. The mixture was stirred for one hour, admixed with 2.6 gof 4-amidino-2-methoxyphenol methanesulfonate, and further stirredovernight at room temperature. After addition of ethyl ether to thereaction mixture, the supernatant was removed to obtain an oilysubstance as the residue. The oily substance was dissolved in DMF, thenfreed from insolubles by filtration, and mixed with ethyl ether toobtain 4.0 g of a colorless oily substance. This substance was dissolvedin water by heating, then treated with activated carbon, and mixed withacetone to isolate 3.5 g of 4-amidino-2-methoxyphenyl6-guanidinocaproate methanesulfonate hydrochloride in the form ofcolorless oil.

EXAMPLE 12 Synthesis of 4-amidino-2-methoxycarbonylphenyltrans-4-benzyloxycarbonylaminomethylcyclohexanecarboxylate ##STR30##

Into 40 ml of anhydrous pyridine, was dissolved 4.3 g oftrans-4-benzyloxycarbonylaminomethylcyclohexanecarboxylic acid. To thesolution, while being cooled in ice, was added 3.7 g of DCC. To themixture which had been stirred for 30 minutes, was added 4.1 g of methyl5-amidinosalicylate methanesulfonate. The mixture was stirred overnightat room temperature. The precipitate which was formed was separated byfiltration and washed with pyridine. Ethyl ether was added to thefiltrate and the precipitated white crystals were washed with ethylether and dissolved in DMF. The colorless crystals separated from theDMF solution by the addition of ethyl ether were recrystallized fromethanol to obtain 4.3 g of a colorless powder of4-amidino-2-methoxycarbonylphenyltrans-4-benzyloxycarbonylamino-methylcyclohexanecarboxylatemethanesulfonate.

EXAMPLE 13 Synthesis of 4-amidino-2-methyoxycarbonylphenyltrans-4-aminomethylcyclohexanecarboxylate ##STR31##

To 9.0 ml of a 30% hydrogen bromide-acetic acid mixture, was added 2.8 gof 4-amidino-2-methoxycarbonylphenyltrans-4-benzyloxycarbonylaminomethylcyclohexanecarboxylatemethanesulfonate. The mixture was stirred for one hour at roomtemperature, meanwhile the crystals dissolved in a few minutes, forminga uniform yellow solution. The reaction mixture was mixed with ethylether, and the crystals were collected by filtration, washed with ethylether, and dried to obtain 3.1 g a dried product. The dried product wasrecrsytallized from ethanol to obtain 1.3 g of colorless granularcrystals of 4-amidino-2-methoxycarbonylphenyltrans-4-aminomethylcyclohexane carboxylate dihydrobromide.

EXAMPLE 14

The following compounds were obtained by the procedures similar to thoseof Examples 7 to 13: ##STR32##

EXAMPLE 15a Synthesis of 4-amidino-3-methylphenyl benzoate ##STR33##

Into 4 ml of anhydrous pyridine, was dissolved 300 mg of4-amidino-3-methylphenol methanesulfonate. To the solution, while beingcooled in ice and stirred, was added slowly dropwise 171 mg of benzoylchloride. The mixture was stirred for one hour at room temperature. Thesolid matter precipitated from the reaction mixture was separated byfiltration and washed with a small volume of pyridine. The oilysubstance separated out of the filtrate by the addition of ethyl etherwas dissolved in water and admixed with a saturated sodiumhydrogencarbonate solution to precipitate a white solid substance. Thissubstance was collected by filtration and washed with water, then withethyl ether to obtain 150 mg of the carbonate of captioned compound.

IR, ν_(max).^(KBr), cm⁻¹ : 3350, 2925, 2600, 1710, 1600, 1580.

The above carbonate was suspended in methanol and admixed with 60 mg ofmethanesulfonic acid. Upon addition of ethyl ether, there were obtained160 mg of a white powder of 4-amidino-3-methylphenyl benzoatemethanesulfonate.

EXAMPLE 15-b

The 4-amidino-3-methylphenol methanesulfonate employed in Example 15-ahad been synthesized according to the following reaction scheme:##STR34##

I. Synthesis of 4-hydroxy-2-methylbenzoic acid

Into 67 ml of pyridine, was dissolved 20 g of4-hydroxy-2-methylacetophenone. After addition of 33.8 g of iodine, thesolution was heated for 30 minutes on a boiling water bath and leftstanding overnight at room temperature. A pale brown solid precipitatedfrom the reaction mixture was washed out of the reaction vessel withethyl ether, then washed with water, and dried to obtain 38 g of anintermediate.

IR, ν_(max).^(KBr), cm⁻¹ : 3180, 1670.

In 1.9 liters of a 50% aqueous ethanol, was suspended 35.7 g of theabove intermediate. To the suspension was added 38 g of sodiumhydroxide. After having been heated for one hour on a boiling waterbath, the reaction mixture was concentrated to half the volume andwashed with ethyl acetate. The aqueous layer was acidified withconcentrated hydrochloric acid and extracted with ethyl acetate. Theorganic layer was dried over anhydrous magnesium sulfate and freed fromthe solvent by distillation under reduced pressure to obtain 26.9 g of apale brown oily substance. This oily substance was treated with an ethylether-petroleum ether mixture to yield 12.4 g of a pale brown solid.

IR, ν_(max).^(KBr), cm⁻¹ : 3380, 2950, 2600, 1655, 1600.

In 100 to 150 ml of methanol, was dissolved 12.1 g of the above solidand to the resulting solution was added 1.2 g of a 10% palladium-carbon.To the mixture, while being stirred at room temperature, was addedcarefully 9.5 g of sodium borohydride in small portions. After stirringfor 30 minutes, the palladium-carbon was removed by filtration. Thefiltrate was concentrated under reduced pressure and admixed with water.The resulting aqueous solution was acidified with concentratedhydrochloric acid and extracted with ethyl ether. The organic layer waswashed with a saturated aqueous sodium chloride solution, dried overanhdyrous magnesium sulfate, and freed from the solvent by distillationunder reduced pressure. The residue was recrystallized from hot water toobtain 8.5 g of 4-hydroxy-2-methylbenzoic acid.

Melting point: 175°-177° C.

IR, ν_(max).^(KBr), cm⁻¹ : 3600-2000, 1665, 1600, 1575.

NMR, CD₃ COCD₃, δ: 2.60 (3H, s), 6.77 (2H, m), 7.67 (2H, br), 8.00 (1H,d, J=9.0 Hz).

II. Synthesis of 4-acetyloxy-2-methylbenzoic acid

Into 40 ml of anhydrous ethyl ether, was dissolved 7.1 g of4-hydroxy-2-methylbenzoic acid followed by 21.3 g of acetic anhydride.The solution was stirred for 2.4 hours at room temperature. The reactionmixture was freed from the solvent under reduced pressure. The residuewas admixed with hot water, then allowed to cool, and extracted withethyl ether. The organic layer was washed with 2% hydrochloric acid,dried over anhydrous magnesium sulfate, and freed from the solvent bydistillation under reduced pressure. The residue was recrystallized froman ethyl ether-petroleum ether mixture to obtain 7.5 g of4-acetyloxy-2-methylbenzoic acid.

Melting point: 136°-137.5° C.

IR, ν_(max).^(KBr), cm⁻¹ : 3250-2400, 1745, 1670, 1213.

NMR, CDCl₃, δ: 2.33 (3H, s), 2.70 (3H, s), 7.10 (2H, m), 8.17 (1H, d,J=9.0 Hz), 11.42 (1H, br).

III. Synthesis of 4-acetyloxy-2-methylbenzoyl chloride

In 60 ml of anhydrous ethyl ether, was suspended 6.2 g of4-acetyloxy-2-methylbenzoic acid. To the suspension, was added 8.0 g ofphosphorus pentachloride. The suspension was stirred for 3 hours at roomtemperature. The reaction mixture was freed from the solvent bydistillation under reduced pressure, admixed again with ethyl ether, andfreed from the solvent by distillation to obtain4-acetyloxy-2-methylbenzoyl chloride.

IR, ν_(max).^(neat), cm⁻¹ : 1760, 1190.

IV. Synthesis of 4-acetyloxy-2-methylbenzamide

The acyl chloride prepared above was dissovled in 100 ml of anhydrousethyl ether. Dried gaseous ammonia was introduced into the stirredsolution and the stirring was continued for 20 to 30 minutes. The whitecrystals precipitated from the reaction mixture were collected byfiltration, washed with ethyl ether, and dissolved in ethyl acetate. Theresulting solution was washed with water, dried over anhydrous magnesiumsulfate, and freed from the solvent by distillation under reducedpressure. The residue was washed with ethyl ether to obtain 4.9 g ofwhite needle crystals of 4-acetyloxy-2-methylbenzamide.

mp: 169.5°-171° C.

IR, ν_(max).^(KBr), cm⁻¹ : 3360, 3175, 1750, 1650, 1215.

NMR, DMSO-d₆, δ: 2.23 (3H, s), 2.37 (3H, s), 7.00 (2H, m), 7.42 (1H, d,J=9.0 Hz), 7.13-7.90 (2H, br).

V. Synthesis of 4-iminoethoxymethyl-3-methylphenyl acetate hydrogenboron tetrafluoride

To a stirred suspension of 3.9 g of 4-acetyloxy-2-methylbenzamide in 40ml of anhydrous methylene chloride, was added slowly dropwise a solutionof 3.8 g of Meerwein reagent [(C₂ H₅)₃ O⁺ BF₄ ⁻ ] in 15 ml of anhydrousmethylene chloride. To the reaction mixture which had been stirred for24 hours at room temperature, was added a large volume of anhydrousethyl ether. A white solid substance which was precipitated wascollected by filtration and dried to obtain 5.8 g of4-iminoethoxymethyl-3-methylphenyl acetate hydrogen boron tetrafluoride.

Melting point: 182°-184° C.

IR, ν_(max).^(KBr), cm⁻¹ : 3330, 3190, 2920, 1755, 1690, 1600, 1050.

NMR, DMSO-d₆, δ: 1.50 (3H, t, J=7.0 Hz), 2.32 (3H, s), 2.48 (3H, s),4.65 (2H, q, J=7.0 Hz), 7.23 (2H, m), 7.73 (1H, d, J=9.0 Hz).

VI. Synthesis of 4-amidino-3-methylphenol methanesulfonate

To 100 ml of ethanol, was added 5.8 g of4-iminoethoxymethyl-3-methylphenyl acetate hydrogen boron tetrafluoride.Into the mixture, while being stirred, was introduced gaseous ammonia.The mixture was heated under reflux for 4 to 5 hours. The reactionmixture was freed from the solvent by distillation under reducedpressure. To the residue, was added ethanol followed by methanesulfonicacid. After addition of a small volume of ethyl ether, the mixture wasfreed from the insoluble solids by filtration. The filtrate was freedfrom the solvent by distillation under reduced pressure, leaving behinda viscous oily substance which was crystallized by treating with anacetone-ethyl ether mixture to obtain 1.0 g of a white powder of4-amidino-3-methylphenol methanesulfonate.

mp: 120°-122° C.

IR, ν_(max).^(KBr), cm⁻¹ : 3300, 3130, 1655, 1610, 1228, 1210, 1190.

NMR, DMSO-d₆, δ: 2.33 (3H, s), 2.43 (3H, s), 6.80 (2H, m), 7.30 (1H, d,J=9.0 Hz), 8.78-9.28 (4H, br), 9.67-10.67 (1H, br).

EXAMPLE 16-a Synthesis of 4-amidino-2-methoxyphenyl benzoate ##STR35##

Into 100 ml of anhydrous pyridine, was dissolved 15.7 g of4-amidino-2-methoxyphenol methanesulfonate. To the solution, while beingcooled in and stirred, was added slowly 8.4 g of benzoyl chloride. Afterthe addition, the mixture was stirred overnight at room temperature. Theprecipitate was separated by filtration and washed with pyridine. Ethylether was added to the filtrate to allow an oily substance to separatefrom the filtrate. The oily substance was washed 2 or 3 times with ethylether, then dissolved in water, and, while being stirred, admixed with asaturated aqueous sodium hydrogen carbonate solution to precipitate thecarbonate of captioned compound. The carbonate was collected byfiltration, washed with water, then with ethyl ether, and dried toobtain 20.7 g of the carbonate. The carbonate was suspended in 50 ml ofmethanol and, while being cooled in ice, admixed with 6.9 g ofmethanesulfonic acid. The crystals once dissolved and then precipitatedagain. After addition of ethyl ether, there were obtained 16.4 g ofcolorless granular crystals of 4-amidino-2-methoxyphenyl benzoatemethanesulfonate.

EXAMPLE 16-b

The 4-amidino-2-methoxyphenol methanesulfonate employed above wassynthesized by the route as shown below: ##STR36##

I. Synthesis of 4-cyano-2-methoxyphenol

This compound was synthesized by the Schmidt reaction [J.A.C.S., 70,2293 (1948)] from 25.0 g of vanillin, 110 ml of concentrated sulfuricacid and 13.5 g of sodium azide. The yield of 4-cyano-2-methoxyphenolwas 9.4 g.

mp: 84°-86° C. (89°-90° C., as reported in the literature).

IR, ν_(max).^(KBr), cm⁻¹ : 3360, 2220.

II. Synthesis of 4-methoxyiminomethyl-2-methoxyphenol

In 50 ml of anhydrous methanol, was dissolved 7.5 g of4-cyano-2-methoxyphenol. The solution was saturated with dried gaseoushydrogen chloride, while being cooled in ice and stirred, and thenstirred overnight at room temperature to precipitate yellow crystals.After addition of ethyl ether, the crystals were collected byfiltration, washed with ethyl ether and dried to obtain 9.4 g of4-methoxyiminomethyl-2-methoxyphenyl hydrochloride.

mp: 123°-124.5° C.

IR, ν_(max).^(KBr), cm⁻¹ : 2920, 1680.

NMR, DMSO-d₆ δ: 3.90 (3H, s), 4.30 (3H, s), 7.07 (1H, d, J=8.5 Hz), 7.68(1H, d, d, J=8.5, 2.0 Hz), 7.90 (1H, d, J=2.0 Hz), 6.80-8.00 (1H, br),11.23-12.00 (1H, br).

III. Synthesis of 4-amidino-2-methoxyphenol

To a mixture of 100 ml of anhydrous methanol and about 50 ml of liquidammonia, was added slowly 8.7 g of 4-methoxyiminomethyl-2-methoxyphenolhydrochloride. The mixture was stirred overnight at room temperature.The colorless crystals precipitated from the reaction mixture werecollected by filtration, washed thoroughly with methanol, and dried toobtain 7.4 g of 4-amidino-2-methoxyphenol.

mp: >240° C.

IR, ν_(max).^(KBr), cm⁻¹ : 3300, 2800, 1680.

Then, to a suspension of 6.6 g of 4-amidino-2-methoxyphenol in 20 ml ofmethanol, was added 4.7 g of methanesulfonic acid. After the crystalshad been dissolved, forming a uniform solution, ethyl ether was added tothe solution and stirred, while cooling in ice, to obtain colorlesscrystals. After recrystallization from ethanol, there were obtained 8.1g of prismatic crystals of 4-amidino-2-methoxyphenol methanesulfonate.

mp: 151°-152° C.

IR, ν_(max).^(KBr), cm⁻¹ : 3500-2800 (several lines), 1660, 1600, 1190.

NMR, DMSO-d₆, δ: 2.47 (3H, s), 3.90 (3H, s), 7.00 (1H, s, J=8.5 Hz),7.43 (2H, m), 8.67-9.33 (4H, br), 10.27 (1H, br, s).

EXAMPLE 17-a Synthesis of 4-amidino-2-carboxyphenyl benzoate ##STR37##

To a suspension of 3.0 g of 5-amidinosalicylic acid methanesulfonate in40 ml of dried pyridine, while being cooled in ice and stirred, wasadded slowly 1.5 g of benzoyl chloride. The mixture was stirred for 3hours at room temperature. The crystals gradually dissolved, forming aclear pale yellow solution, and an oily substance separated out. Afteraddition of ethyl ether to the reaction mixture and removal of thesupernatant, the oily substance was washed several times with ethylether and dissolved in water. Upon addition of a saturated aqueoussodium hydrogencarbonate solution, pale yellow crystals precipitated.After cooling in ice, the crystals were collected by filtration, washedwith a small volume of water, and dried to obtain 1.0 g of the crystals.The crystals were suspended in a small volume of methanol and allowed todissolve by the addition of 0.4 g of methanesulfonic acid. Ethyl etherwas added to the solution with stirring to obtain 0.8 g of a colorlesspowder of 4-amidino-2-carboxyphenyl benzoate methanesulfonate.

EXAMPLE 17-b

The 5-amidinosalicylic acid methanesulfonate employed above wassynthesized as shown in the following reaction scheme: ##STR38##

I. Synthesis of 5-methoxyiminomethylsalicylic acid

A solution of 6.0 g of 5-cyanosalicylic acid in 60 ml of anhydrousmethanol, while being cooled in ice and stirred, was saturated withdried gaseous hydrogen chloride and stirred overnight at roomtemperature. Anhydrous ethyl ether was added to the reaction mixture toobtain 4.3 g of white crystals of 5-methoxyiminomethylsalicylic acidhydrochloride.

Melting point: 282°-284° C. (decomp.).

IR, ν_(max).^(KBr), cm⁻¹ : 3280, 2970, 2720, 1660.

NMR, DMSO-d₆, δ: 3.07 (3H, s), 7.02 (1H, d, J=8.5 Hz), 8.07 (1H, d, d,J=8.5, 2.0 Hz), 8.42 (1H, d, J=2.0 Hz), 6.87-8.67 (2H, br), 10.13-11.33(2H, br).

II. Synthesis of 5-amidinosalicylic acid

To a mixture of 40 ml of methanol and 20 ml of liquid ammonia, was added4.0 g of 5-methoxyiminomethylsalicylic acid hydrochloride. The mixturewas stirred overnight at room temperature. A colorless gelatinoussubstance precipitated from the reaction mixture was washed withmethanol, and washed with a water-acetone (20 ml-80 ml) mixture toobtain 2.6 g of 5-amidinosalicylic acid.

IR, ν_(max).^(KBr), cm⁻¹ : 3370, 3050, 1700, 1615.

To a suspension of 2.5 g of the 5-amidinosalicylic acid, was added 1.7 gof methanesulfonic acid followed by ethyl ether to obtain 3.5 g of5-amidinosalicylic acid methanesulfonate.

mp: ˜260° C. (decomp.).

IR, ν_(max).^(KBr), cm⁻¹ : 3600-2700, 1650.

NMR, DMSO-d₆ δ: 2.43 (3H, s), 7.17 (1H, d, J=8.5 Hz), 7.98 (1H, d, d,J=8.5, 2.0 Hz), 8.37 (1H, d, J=2.0 Hz), 8.77-9.46 (4H, br), 10.20-11.17(2H, br).

EXAMPLE 18-a Synthesis of 4-amidino-2-methoxycarbonylphenyl benzoate##STR39##

Into 40 ml of anhydrous pyridine, was dissolved 4.0 g of methyl5-amidinosalicylate methanesulfonate. To the solution, while beingcooled in ice and stirred, was added 1.9 g of benzoyl chloride. Themixture was stirred overnight at room temperature. The precipitate whichwas formed was separated by filtration and washed with pyridine. Ethylether was added to the filtrate and after a while colorless crystalsprecipitated. The crystals were collected by filtration, washed withethyl ether and dissolved in water. A saturated aqueous sodiumhydrogencarbonate solution was added to the solution while stirring. Theprecipitated colorless crystals were collected by filtration, washedwith water, then with acetone, and dried to obtain 3.8 g of thecarbonate of the captioned compound. To a suspension of the carbonate ina small volume of methanol, was added 1.2 g of methanesulfonic acid. Thecarbonate dissolved with effervescence and immediately thereaftercolorless crystals precipitated. The crystals were recrystallized from amethanol-ethyl ether mixture to obtain 4.1 g of colorless needlecrystals of 4-aminido-2-methoxycarbonylphenyl benzoate methanesulfonate.

EXAMPLE 18-b

The methyl 5-amidinosalicylate methanesulfonate employed above wassynthesized according to the following reaction scheme: ##STR40##

I. Synthesis of methyl 5-bromosalicylate

Into 400 ml of anhydrous methanol, was dissolved 96.0 g of5-bromosalicylic acid. After addition of 20 ml of concentrated sulfuricacid, the mixture was heated under reflux for about 20 hours. Thereaction mixture was freed from the solvent, allowed to cool, andextracted by adding water and ethyl ether. The organic layer was washedwith water, then twice with a saturated aqueous sodium hydrogencarbonatesolution, and finally with a saturated sodium chloride solution. Thewashed organic layer was dried over magnesium sulfate, freed from thesolvent by distillation under reduced pressure to obtain 93.7 g ofcolorless crystals of methyl 5-bromosalicylate.

mp: 48°-50° C.

IR, ν_(max).^(KBr), cm⁻¹ : 3170, 1675.

II. Synthesis of methyl 4-cyanosalicylate

To a mixture of 92.0 g of methyl 4-bromosalicylate and 42.8 g of cuprouscyanide, was added 90 ml of DMF. While being stirred vigorously under anitrogen stream, the mixture was heated at an oil bath temperature of160° to 170° C. for 2 to 3 hours. The reaction mixture was allowed tocool and the green solid was added to water to be finely disintegrated.The disintegrated solid was collected by filtration and wahsedthoroughly with water. The resulting product was extracted several timeswith aqueous ammonia (concentrated ammonia: water=1:5). The aqueousammonia layers were combined and, while being cooled in ice, acidifiedwith 10% hydrochloric acid to obtain colorless crystals. The crystalswere collected by filtration, washed with water, dissolved in ethylacetate, washed twice with water, then three times with a 2% aqueoussodium hydrogencarbonate solution, and finally with a saturated aqueoussodium chloride solution. The organic layer was dried over magnesiumsulfate and freed from the solvent by distillation to obtain colorlescrystals which were recrystallized from ethanol, yielding 45.0 g ofcolorless needle crystals of methyl 5-cyanosalicylate.

mp: 114°-115° C.

IR, ν_(max).^(KBr), cm⁻¹ : 3070, 2220, 1665.

NMR, CDCl₃, δ: 4.03 (3H, s), 7.13 (1H, d, J=9.0 Hz), 7.93 (1H, d, d,J=9.0, 2.0 Hz), 8.23 (1H, d, J=2.0 Hz).

On the other hand, the alkaline layer was acidified with 10%hydrochloric acid to precipitate colorless crystals which wererecrystallized from aqueous ethanol, yielding 6.6 g of colorless needlecrystals of 5-cyanosalicylic acid.

mp: ˜173° C. (decomp.).

IR, ν_(max).^(KBr), cm⁻¹ : 3520, 3470, 3200, ˜3350, 2240, 1680.

III. Synthesis of methyl 5-methoxyiminomethylsalicylate

In 450 ml of anhydrous methanol, was suspended 44.0 g of methyl5-cyanosalicylate. While being cooled in ice and stirred, the suspensionwas saturated with dried gaseous hydrogen chloride. The suspension wasfurther stirred for 2 days at room temperature, then the resultingsolution was concentrated to about 200 ml at a low temperature underreduced pressure, and admixed with ethyl acetate to precipitatecolorless crystals. The crystals were collected by filtration and driedto obtain 41.0 g of methyl 5-methoxyiminomethylsalicylate hydrochloride.

IR, ν_(max) ^(KBr), cm⁻¹ : 3170, 1690, 1630.

NMR, DMSO-d₆ δ: ##STR41## 3.93 (--COOCH₃), 7.07 (d, J=8.5 Hz), 8.12 (d,d, J=8.5, 2.5 Hz), 8.38 (d, J=2.5 Hz).

IV. Synthesis of methyl 5-amidinosalicylate

To a solution prepared by introducing 6.0 g of dried gaseous ammoniainto 200 ml of anhydrous methanol, was added with stirring at roomtemperature 40.0 g of methyl 5-methoxyiminomethylsalicylatehydrochloride. The crystals dissolved, yielding a clear yellow solutionand after 5 to 10 minutes there occurred precipitation of colorlesscrystals. The crystals were collected by filtration and washed withmethanol to obtain 16.8 g of methyl 5-amidinosalicylate.

mp: 226°-229° C. (decomp).

IR, ν_(max).^(KBr), cm⁻¹ : 3360, 3200, 1665.

In 100 ml of methanol, was suspended 16.0 g of the methyl5-amidinosalicylate. To the suspension was added 10.3 g ofmethanesulfonic acid to dissolve the crystals. Ethyl ether was added tothe resulting solution, while being cooled in ice and stirred, to obtain23.0 g of colorless needle crystals of methyl 5-amidinosalicylatemethanesulfonate.

mp: 156°-159° C.

IR, ν_(max).^(KBr), cm⁻¹ : 3300, 3050, 1650, 1200.

NMR, DMSO-d₆, δ: 2.47 (3H, s), 3.93 (3H, s), 7.22 (1H, d, J=8.5 Hz),8.02 (1H, d, d, J=8.5, 2.0 Hz), 8.32 (1H, d, J-2.0 Hz), 8.79-9.48 (4H,br), 11.17 (1H, br).

EXAMPLE 19-a Synthesis of 4-amidino-2-chlorophenyl benzoate ##STR42##

To 30 ml of anhydrous pyridine, was added 2.7 g of4-amidino-2-chlorophenol methanesulfonate. To the mixture, while beingcooled in ice, was added 1.4 g of benzoyl chloride. The mixture wasstirred for 30 minutes, while being cooled in ice, then for 5 hours atroom temperature. The reaction mixture was mixed with 100 ml of ethylether to allow an oily substance to separate out. The oily substance wasdissolved in 20 ml of methanol and poured into a saturated aqueoussodium hydrogencarbonate solution. The precpitated crystals werecollected by filtration and washed with water, then with acetone. Thewashed crystals were added to 20 ml of methanol and admixed with 2.5 gof methanesulfonic acid. The insolubles were removed by filtration and100 ml of ethyl ether was added to the filtrate. The precipitatedcolorless crystals were collected by filtration to obtain 2.5 g of4-amidino-2-chlorophenyl benzoate methanesulfonate.

EXAMPLE 19-b

The 4-amidino-2-chlorophenol methanesulfonate employed above wassynthesized according to the following reaction scheme: ##STR43##

I. Synthesis of 2-chloro-4-cyanophenol

To 10 ml of DMF, were added 9.0 g of 2-chloro-4-bromophenol and 4.7 g ofcuprous cyanide (CuCN). The resulting solutoin was heated at 160° C. for2 hours while passing nitrogen through the solution. The reactionmixture was allowed to cool, admixed with 100 ml of a 10% aqueous sodiumhydroxide solution, and thoroughly stirred. The insolubles were removedby filtration and the filtrate was neutralized with 10% hydrochloricacid. The precipitate was collected by filtration to obtain 4.7 g ofpale yellow crystals of 2-chloro-4-cyanophenol.

mp: 110°-113° C.

IR, ν_(max).^(KBr), cm⁻¹ : 3220, 2240, 1600, 1307.

II. Synthesis of 2-chloro-4-methoxyiminomethylphenol hydrochloride

While being cooled in ice, a solution of 4.5 g of 2-chloro-4-cyanophenolin 50 ml of methanol was saturated with dried gaseous hydrogen chloride(HCl). The solution was left standing overnight at room temperature andmixed with 100 ml of ethyl ether to precipitate crystals which werecollected by filtration to obtain 4.0 g of2-chloro-4-methoxyiminomethylphenol hydrochloride.

mp: 138°-139° C.

IR, ν_(max).^(KBr), cm⁻¹ : 3010, 1680, 1600, 1060.

NMR, DMSO-d₆, δ: 3.05 (3H, s), 5.0-6.0 (b), 7.03-8.23 (3H, m).

III. Synthesis of 4-amidino-2-chlorophenol methanesulfonate

Anhydrous gaseous ammonia (NH₃) was passed through a mixture of 3.5 g of2-chloro-4-methoxyiminomethylphenol hydrochloride and 50 ml of anhydrousmethanol. The mixture was stirred overnight at room temperature andfreed from the solvent by distillation. The residue was dissolved in 20ml of methanol and mixed with 2.5 g of methanesulfonic acid followed by100 ml of ethyl ether to obtain 3.0 g of 4-amidino-2-chlorophenolmethanesulfonate in colorless oily form.

EXAMPLE 20-a Synthesis of 4-amidino-2-nitrophenyl benzoate ##STR44##

Into 40 ml of dried pyridine, was dissolved 4.2 g of4-amidino-2-nitrophenol methanesulfonate. To the solution, while beingcooled in ice and stirred, was added portionwise 2.1 g of benzoylchloride. The solution was stirred overnight at room temperature andremoved of the insolubles by filtration. Ethyl ether was added to thefiltrate to allow an oily substance to separate out. After removal ofthe supernatant, the oily substance was washed a few times with ethylether, and dissolved in water. To the aqueous solution, while beingstirred, was added a saturated aqueous sodium hydrogencarbonate solutionto precipitate the carbonate of the captioned compound. The carbonateprecipitate was collected by filtration, washed with water, then withacetone, and dried to obtain 4.0 g of pale yellow crystals. To thecarbonate crystals suspended in 10 ml of methanol, was added 1.4 g ofmethanesulfonic acid. The mixture turned, with effervescence, into ahomogeneous solution. Upon addition of ethyl ether there were obtained4.1 g of colorless granular crystals of 4-amidino-2-nitrophenyl benzoatemethanesulfonate.

EXAMPLE 20-b

The 4-amidino-2-nitrophenol methanesulfonate used above was synthesizedin the following manner:

To 20 ml of concentrated sulfuric acid, was added 7.6 g of4-amidinophenol hydrochloride. When the evolution of hydrogen chloridegas had ceased, the solution was cooled in an ice-salt bath and 3.0 mlof nitric acid was slowly added to the solution while being stirred. Themixture was then stirred at room temperature for 20 to 30 minutes. Thereaction mixture, orange in color, was diluted by pouring into a largevolume of ice water. The diluted solution was added in small portions toa saturated aqueous sodium hydrogencarbonate solution to precipitateorange needle crystals. The crystals were collected by filtration anddried to obtain 7.6 g of 4-amidino-2-nitrophenol.

mp: >240° C.

IR, ν_(max).^(KBr), cm⁻¹ : 3600-2800, 1650, 1610, 1490, 1275.

In 20 ml of methanol, was suspended 7.3 g of the 4-amidino-2-nitrophenolobtained above. To the suspension was added 5.8 g of methanesulfonicacid. When the crystals had dissolved forming a homogeneous solution,ethyl ether was added to the solution, and the solution was stirredwhile cooling in ice to precipitate pale yellow crystals which wererecrystallized from ethanol, yielding 9.8 g of pale yellow granularcrystals of 4-amidino-2-nitrophenol methanesulfonate.

mp: 158°-159.5° C.

IR, ν_(max).^(KBr), cm⁻¹ : 3380, 3050, 1665, 1620, 1190, 1180.

NMR, DMSO-d₆, δ: 2.48 (3H, s), 7.38 (1H, d, J=8.5 Hz), 8.07 (1H, d, d,J=8.5, 2.0 Hz), 8.48 (1H, d, J=2.0 Hz), 9.00-9.53 (4H, br).

EXAMPLE 21-a Synthesis of 5-amidino-2-benzoyloxybenzenesulfonic acid##STR45##

To 30 ml of dried pyridine, was added 3.0 g of5-amidino-2-hydroxybenzenesulfonic acid. To the mixture, while beingcooled in ice, was slowly added dropwise 2.0 g of benzoyl chloride.After the addition, the mixture was stirred overnight at roomtemperature. The insolubles deposited from the reaction mixture wereseparated by filtration, washed with pyridine, then with water, finallywith acetone, and suspended in methanol. The insolubles were removed byfiltration, and ethyl ether was added to the filtrate to precipitate acolorless solid. The solid was collected by filtration andrecrystallized from a methanol-ethyl ether mixture to obtain5-amidino-2-benzoyloxybenzenesulfonic acid in colorless solid form.

EXAMPLE 21-b

The 5-amidino-2-hydroxybenzenesulfonic acid employed above was obtainedin the following manner.

To 15 ml of 60% fuming sulfuric acid, while being cooled in ice, wasadded slowly 10.0 g of 4-amidinophenol hydrochloride. After theaddition, the mixture was stirred at room temperature for 4 hours, thenpoured slowly into 200 ml of ice water, and stirred for a while. Thecolorless solid which was precipitated was collected by filtration,washed with water, then with acetone, and dried to obtain 10.2 g of5-amidino-2-hydroxybenzenesulfonic acid.

mp: >300° C.

IR, ν_(max).^(KBr), cm⁻¹ : 3600-2600, 1670, 1610, 1230, 1165.

NMR, NaOD, δ: 6.81 (1H, d, J=9.0 Hz), 7.64 (1H, d, d, J=9.0, 3.0 Hz),8.13 (1H, d, J=3.0 Hz).

EXAMPLE 22-a Synthesis of 4-amidino-2-benzoylphenyl benzoate ##STR46##

Into 10 ml of dried pyridine, was dissolved 1.0 g of4-amidino-2-benzoylphenol methanesulfonate. To the solution, while beingcooled in ice and stirred, was added dropwise 422 mg of benzoylchloride. The mixture was then stirred at room temperature for 3 hours.The reaction mixture was freed from insolubles by filtration and ethylether was added to the filtrate to throw out an oily substance. The oilysubstance was dissolved in water, and the resulting aqueous solution wasadded to a saturated aqueous sodium hydrogencarbonate solution, whilebeeing cooled in ice and stirred. The precipitated white crystals werecollected by filtration, washed with water, then with acetone, and driedto obtain 854 mg of 4-amidino-2-benzoylphenyl benzoate carbonate.

IR, ν_(max).^(KBr), cm⁻¹ : 3375, 3025, 2625, 1730, 1655, 1600.

To a suspension of 854 mg of the above carbonate in a small volume ofmethanol, was added 242 mg of methanesulfonic acid to form a homogeneoussolution. Ethyl ether was added to the solution and triturated whilecooling in ice to obtain 920 mg of a white powder of4-amidino-2-benzoylphenyl benzoate methanesulfonate.

mp: ˜160° C.

IR, ν_(max).^(KBr), cm⁻¹ : 3275, 3100, 1730, 1675, 1650.

NMR, DMSO-d₆, δ: 2.48 (3H, s), 7.25-8.33 (13H, m), 9.21-9.71 (4H, br).

EXAMPLE 22-b

The 4-amidino-2-benzoylphenol methanesulfonate employed above wassynthesized according to the following reaction scheme: ##STR47##

I. Synthesis of 4-bromophenyl benzoate

To a solution of 360 g of 4-bromophenol in 4.3 liters of ethyl acetate,was added 326 ml of triethylamine. To the mixture, while being cooled inice and stirred, was added dropwise 300 g of benzoyl chloride over aperiod of 90 minutes. After two hours of stirring, water was added tothe reaction mixture to remove the triethylamine hydrochloride. Theethyl acetate layer was washed successively with a dilute aqueous alkalisolution, dilute hydrochloric acid, and saturated aqueous sodiumchloride solution, then dried over anhydrous magnesium sulfate, andfreed from the solvent by distillation. The residue was washed withethanol and dried to obtain 500 g of 4-bromophenyl benzoate.

mp: 98°-100° C.

IR, ν_(max).^(KBr), cm⁻¹ : 1730.

NMR, CDCl₃, δ: 7.08 (2H, d, J=9.0 Hz), 7.50 (5H, m), 8.15 (d, d, J=8.0,3.0 Hz).

II. Synthesis of 2-benzoyl-4-bromophenol

An intimate mixture was prepared from 500 g of 4-bromophenyl benzoateand 317 g of anhydrous aluminum chloride by grinding together in amortar. The mixture was gradually heated with stirring to form ahomogeneous solution. The temperature of the solution was furtherelevated to a level of 140°-150° C. and kept at this level for 15 to 20minutes. After having been left to cool down, the reaction mixture wascarefully added with stirring to a mixture of 2.6 kg of ice and 1.3liters of concentrated hydrochloric acid. The precipitated yellowcrystals were collected by filtration, washed with water, and shakentogether with a 10% aqueous potassium hydroxide solution and ethylether. The alkali layer was acidified with concentrated hydrochloricacid to precipitate yellow crystals which were recrystallized fromethanol, giving 373 g of yellow needle crystals of2-benzoyl-4-bromophenol.

mp: 109°-110° C.

IR, ν_(max).^(KBr), cm⁻¹ : 3050, 1618, 1595.

NMR, CDCl₃, δ: 6.97 (1H, d, J=8.0 Hz), 7.57 (7H, m), 11.92 (1H, br-s).

III. Synthesis of 2-benzoyl-4-cyanophenol

To a mixture of 370 g of 2-benzoyl-4-bromophenol and 146 g of cuprouscyanide, was added 370 ml of DMF. The mixture was refluxed for 4 hours,while being stirred vigorously under a nitrogen stream. After havingbeen left cooling down, the reaction mixture was poured into ice water.The precipitated solid matter was dissolved in a 10% aqueous sodiumhydroxide solution, removed of the insolubles by filtration, andacidified with concentrated hydrochloric acid to obtain a yellow solidsubstance. This substance was dissolved in ethanol, freed from theinsolubles, admixed with water to precipitate crystals which were dried,yielding 214 g of yellow crystals of 2-benzoyl-4-cyanophenol.

mp: 106°-108° C.

IR, ν_(max).^(KBr), cm⁻¹ : 3050, 2220, 1620, 1590.

NMR, CDCl₃, δ: 7.63 (8H, br-s).

Mass spectrum, m/e: 223 (M⁺).

IV. Synthesis of 2-benzoyl-4-methoxyiminomethylphenol hydrochloride

A suspension of 214 g of 2-benzoyl-4-cyanophenol in 1.7 liters ofanhydrous methanol was saturated with anhydrous hydrogen chloride, whilebeing cooled in ice and stirred. After having been stirred overnight atroom temperature, the mixture was mixed with a large volume of ethylether. The precipitated crystals were collected by filtration and driedto yield 156 g of 2-benzoyl-4-methoxyiminomethylphenol hydrochloride.

mp: 131°-132° C.

IR, ν_(max).^(KBr), cm⁻¹ : 3000, 1655, 1600.

NMR, 60 MC, DMSO-d₆, δ (ppm): 3.05 (s), 6.97-8.33 (m), 10.33-11.33 (br).

V. Synthesis of 4-amidino-2-phenyliminomethylphenol

In one liter of anhydrous methanol, was suspended 156 g of2-benzoyl-4-methoxyiminomethylphenol hydrochloride. While stirring andintroducing gaseous ammonia, the suspension was heated at 60° C. for 2to 3 hours. After removal of the solvent by distillation, the residuewas dissolved in a saturated aqueous sodium hydrogencarbonate solutionand triturated while being cooled in ice, to precipitate yellowcrystals. The crystals were thoroughly washed with water, then withacetone, and dried to obtain 125 g of4-amidino-2-phenyliminomethylphenol carbonate.

IR, ν_(max).^(KBr), cm⁻¹ : 3325, 3050, 1655, 1595.

VI. Synthesis of 4-amidino-2-benzoylphenol methanesulfonate

Into one liter of 3N hydrochloric acid, was dissolved 125 g of4-amidino-2-phenyliminomethylphenol carbonate. The solution was heatedfor one hour on a boiling water bath. The reaction mixture was cooled inice to precipitate white crystals. The crystals were collected byfiltration, removed thoroughly of adhered water, washed with anacetone-ethyl ether mixture, and dried to obtain4-amidino-2-benzoylphenol hydrochloride.

mp: 219°-224° C.

IR, ν_(max).^(KBr), cm⁻¹ : 3350, 3100, 1668, 1632, 1600.

In 200 ml of methanol, was suspended the 4-amidino-2-benzoylphenolhydrochloride obtained above. To the suspension was added 60 g ofmethanesulfonic acid followed by ethyl ether. The precipitated paleyellow crystals were collected by filtration and dried to obtain 109 gof 4-amidino-2-benzoylphenol methanesulfonate.

mp: 186°-189° C. (The yield based on 4-bromophenol was 15.2%).

IR, ν_(max).^(KBr), cm⁻¹ : 3500, 3280, 1675, 1630, 1600, 1200.

NMR, DMSO-d₆, δ: 2.74 (3H, s), 7.20 (1H, d, J=8.0 Hz), 7.40-8.10 (8H,m), 8.86-9.36 (4H, br).

EXAMPLE 23-a Synthesis of 4-amidino-2-benzoylaminophenyl benzoate##STR48##

Into 30 ml of pyridine, was dissolved 1.7 g of 4-amidino-2-aminophenoldimethanesulfonate. to the solution, while being cooled in ice andstirred, was added 1.8 g of benzoyl chloride. The mixture was stirredfor 30 minutes while cooling in ice and 2 hours at room temperature. Thereaction mixture was admixed with about 100 ml of ethyl ether to allow acolorless oily substance to separate out. The solvent was removed bydecantation and the residue was dissolved in a small volume of ethanol.Upon addition of a saturated aqueous sodium hydrogencarbonate solution,colorless crystals of 4-amidino-2-benzoylaminophenyl benzoate carbonatewere precipitated. The crystals were collected by filtration, washedwith water, then with acetone, and suspended in ethanol. On addition ofmethanesulfonic acid, the suspension turned into a clear solution. Ethylether was added to the solution to precipitate crystals. The crystalswere collected by filtration and recrystallized from an ethanol-ethylether mixture to obtain 1.4 g of colorless crystals of4-amidino-2-benzoylaminophenyl benzoate methanesulfonate.

EXAMPLE 23-b

The 4-amidino-2-aminophenol dimethanesulfonate employed above wassynthesized in the following manner:

To 200 ml of ethanol, were added 15 g of 4-amidino-2-nitrophenolmethanesulfonate and 1 g of a 10% palladium-carbon. While introducinghydrogen, the mixture was vigorously stirred until no more hydrogen hadbeen absorbed (about 3700 ml of hydrogen were absorbed). The reactionmixture was removed of the insolubles and concentrated to about 50 ml.To the concentrate was added 6.2 g of methanesulfonic acid followed by200 ml of ethyl ether. The precipitated crystals were collected byfiltration to obtain 13 g of 4-amidino-2-aminophenyl dimethanesulfonate.

mp: 195°-197° C.

IR, ν_(max).^(KBr), cm⁻¹ : 3700-2800, 1665, 1625, 1190, 1040.

NMR, DMSO-d₆, δ: 2.40 (6H, s), 7.07-7.60 (m), 8.73-9.33 (4H, br).

EXAMPLE 24 Synthesis of 4-amidino-2-methoxyphenyl cinnamate ##STR49##

To a solution of 6.2 g of 4-amidino-2-methoxyphenol methanesulfonate in30 ml of dried pyridine, while being cooled in ice and stirred, wasadded 3.9 g of cinnamoyl chloride. Immediately after the addition acolorless solid substance precipitated from the reaction mixture. After3 hours of stirring at room temperature, ethyl ether was added to themixture and the precipitate was collected by filtration. The precipitatewas dissolved in methanol and mixed with a saturated aqueous sodiumbicarbonate solution to precipitate a white gelatinous substance. Thegelatinous substance was collected by filtration, washed with water,then with acetone and dried to obtain 6.3 g of the carbonate of thecaptioned compound. Upon addition of 2.3 g of methanesulfonic acid tothe carbonate suspended in 60 ml of methanol, a change in crystal formof the carbonate took place accompanied by effervescence. The suspensionwas heated to dissolve the crystals and then cooled to obtain 6.3 g ofcolorless needle crystals of 4-amidino-2-methoxyphenyl cinnamatemethanesulfonate.

EXAMPLE 25 Synthesis of 4-amidino-2-methoxyphenyl 3-phenylpropionate##STR50##

(a) Into 50 ml of dried pyridine, was dissolved 1.5 g of3-phenylpropionic acid. After addition of 3.1 g of DCC, the mixture wasstirred for 30 minutes, then admixed with 2.62 g of4-amidino-2-methoxyphenol methanesulfonate and stirred overnight. Thereaction mixture was freed from insolubles by filtration and admixedwith ethyl ether. The precipitate which was formed was recrystallizedfrom ethanol to obtain 2.7 g of colorless prismatic crystals of4-amidino-2-methoxyphenyl 3-phenylpropionate methanesulfonate.

(b) To 100 ml of methanol, were added 2.0 g of 4-amidino-2-methoxyphenylcinnamate methanesulfonate and 0.5 g of a 10% palladium-carbon. Hydrogenwas fed to the mixture which was stirred vigorously to facilitateabsorption. The reaction mixture was freed from the insolubles byfiltration and from the solvent by distillation. The residue wasrecrystallized from ethanol to obtain 1.5 g of the same4-amidino-2-methoxyphenyl 3-phenylpropionate methanesulfonate.

EXAMPLE 26

The following compounds were obtained by the procedures similar to thoseof Examples 15 to 25: ##STR51##

EXAMPLE 27 Synthesis of 4-amidino-2-benzoylphenyl 4-benzyloxybenzoate##STR52##

To a mixture of 3.4 g of 4-benzyloxybenzoic acid and 50 ml of driedpyridine, while being cooled in ice, was added 3.7 g of DCC. Afterhaving been stirred for 30 minutes, the mixture was admixed with 5.0 gof 4-amidino-2-benzoylphenol methanesulfonate and stirred overnight atroom temperature. The reaction mixture was freed from the insolubles byfiltration and mixed with ethyl ether. The precipitated insolublesubstance was recrystallized from a methanol-ethyl ether mixture toobtain 5.2 g of colorless crystals of 4-amidino-2-benzoylphenyl4-benzyloxybenzoate methanesulfonate.

EXAMPLE 28 Synthesis of 4-amidino-2-benzoylphenyl 4-hydroxybenzoate##STR53##

To 25 ml of acetic acid, was added 2.7 g of 4-amidino-2-benzoylphenyl4-benzyloxybenzoate methanesulfonate followed by 1 ml of anisole. To themixture cooled in ice, was added 13.5 g of a 30% solution of hydrogenbromide in acetic acid. The mixture was stirred for 5 hours and mixedwith ethyl ether. The precipitate was collected by filtration andrecrystallized from a methanol-ethyl ether mixture to obtain 1.4 g of4-amidino-2-benzoylphenyl 4-hydroxybenzoate hydrobromide.

EXAMPLE 29-a Synthesis of 4-amidino-2,6-dibromophenyl3,4-methylenedioxybenzoate ##STR54##

To a solution of 5 g of 4-amidino-2,6-dibromophenol in 100 ml ofpyridine, while being cooled in ice and stirred, was added 2.4 g ofpiperonyl chloride. The mixture was stirred for 30 minutes while beingcooled in ice, then for 3 hours at room temperature, and mixed withabout 300 cc of ethyl ether. The precipitate which was formed wascollected by filtration and recrystallized from ethanol to obtain 4.8 gof colorless crystals of 4-amidino-2,6-dibromophenyl3,4-methylenedioxybenzoate methanesulfonate.

EXAMPLE 29-b

The 4-amidino-2,6-dibromophenol methanesulfonate employed above wasobtained in the following manner:

To a solution of 5.2 g of 4-amidinophenol hydrochloride in 100 ml ofwater, while being stirred, was added dropwise 9.6 g of bromine (Br₂).After 3 hours of stirring at room temperature, a saturated aqueoussodium bicarbonate solution and an aqueous sodium thiosulfate solutionwere added to the reaction mixture. The crystals which were precipitatedwere collected by filtration, suspended in ethanol, and mixed withmethanesulfonic acid. The suspension once turned into a clear solutionbut soon white crystals separated out of the solution. The crystals werecollected by filtration and recrystallized from ethanol to obtain 6.4 gof colorless crystals of 4-amidino-2,6-dibromophenol.

mp: 215°-217° C.

IR, ν_(max).^(KBr), cm⁻¹ : 3650-2500, 1690, 1630, 1455.

NMR, DMSO-d₆, δ: 2.49 (3H, s), 8.13 (2H, s), 9.03-9.46 (4H, br).

EXAMPLE 30

The following compounds were obtained by the procedures similar to thoseof Examples 15 to 25 and 29: ##STR55##

EXAMPLE 31 Synthesis of 4-amidino-2-benzoylphenyl 4-acetyloxycinnamate##STR56##

To a mixture of 3.1 g of 4-acetyloxycinnamic acid and 50 ml of driedpyridine, while being cooled in ice, was added 3.7 g of DCC. To themixture, after having been stirred for 30 minutes, was added 5.0 g of4-amidino-2-benzoylphenol methanesulfonate. The mixture was stirredovernight at room temperature. The insolubles precipitated from thereaction mixture were collected by filtration and mixed with DMF. Ethylether was added to the supernatant to precipitate an insoluble substancewhich was recrystallized from ethanol, yielding 4.7 g of colorlesscrystals of 4-amidino-2-benzoylphenyl 4-acetyloxycinnamatemethanesulfonate.

EXAMPLE 32 Synthesis of 4-amidino-2-benzoylphenyl3-(4-acetyloxy)phenylpropionate ##STR57##

The catalytic reduction of 2.6 g of 4-amidino-2-benzoylphenyl4-acetyloxyphenylcinnamate methanesulfonate was carried out in 25 ml ofDMF using 500 mg of a 10% palladium-carbon. The reaction mixture wasfreed from the palladium-carbon by filtration and mixed with ethylether. The precipitate which was formed was recrystallized from amethanol-ethyl ether mixture to obtain 1.01 g of colorless crystals of4-amidino-2-benzoylphenyl 3-(4-acetyloxy)phenylpropionatemethanesulfonate.

EXAMPLE 33 Synthesis of 4-amidino-2-benzoylphenyl 4-acetylaminobenzoate##STR58##

To a solution of 1.79 g of 4-acetylaminobenzoic acid in 50 ml of driedpyridine, was added 3.1 g of DCC. The mixture was stirred for 30 minuteswhile being cooled in ice. After addition of 3.36 g of4-amidino-2-benzoylphenol methanesulfonate, the mixture was furtherstirred overnight. The reaction mixture was removed of the insolublesand mixed with ethyl ether to obtain a colorless solid substance whichon recrystallization from methanol yielded 0.9 g of colorless crystalsof 4-amidino-2-benzoylphenyl 4-acetylaminobenzoate methanesulfonate.

EXAMPLE 34 Synthesis of 4-amidino-2-methoxyphenyl4-benzyloxycarbonylaminomethylbenzoate ##STR59##

To a solution of 3.7 g of 4-benzyloxycarbonylaminomethylbenzoic acid in40 ml of dried pyridine, was added 3.1 g of DCC with cooling in ice. Themixture was stirred for 30 minutes. After addition of 3.1 g of4-amidino-2-methoxyphenol methanesulfonate, the mixture was furtherstirred overnight at room temperature. The reaction mixture was removedof the insolubles and mixed with ethyl ether to precipitate a colorlesssolid substance which on recrystallization from a methanolethyl ethermixture gave 3.2 g of colorless crystals of 4-amidino-2-methoxyphenyl4-benzyloxycarbonylaminomethylbenzoate methanesulfonate.

EXAMPLE 35 Synthesis of 4-amidino-2-methoxyphenyl 4-aminomethylbenzoate##STR60##

To 1.5 g of 4-amidino-2-methoxyphenyl4-benzyloxycarbonylaminomethylbenzoate methanesulfonate, was added 15 mlof acetic acid followed by 1 ml of anisole. To the mixture, while beingcooled in ice, was added 3.0 ml of an acetic acid solution containing30% of hydrogen bromide. The mixture was then stirred overnight at roomtemperature. The insoluble substance precipitated from the reactionmixture was collected by filtration and recrystallized from amethanol-ethyl ether mixture to obtain 1.1 g of colorless crystals of4-amidino-2-methoxyphenyl 4-aminomethylbenzoate dihydrobromide.

EXAMPLE 36

The following compounds were obtained by the procedures similar to thoseof Examples 34 and 35: ##STR61##

EXAMPLE 37 Synthesis of 4-amidino-2-methoxyphenyl4-(4-aminophenyl)butyrate ##STR62##

A mixture of 2.4 g of 4-(4-nitrophenyl)butyrate methanesulfonate, 30 mlof dried DMF, 0.5 g of a 10% palladium-carbon, and 0.6 g ofmethanesulfonic acid was subjected to catalytic reduction. The reactionmixture was freed from the insolubles by filtration and admixed withethyl ether. The solid substance precipitated from the reaction mixturewas collected by filtration, washed with ethyl ether, and recrystallizedfrom ethanol to obtain 1.8 g of a pale yellow powder of4-amidino-2-methoxyphenyl 4-(4-aminophenyl)butyrate dimethanesulfonate.

EXAMPLE 38 Synthesis of 4-amidino-2-benzoylphenyl4-dimethylaminobenzoate ##STR63##

In 50 ml of dried pyridine, was dissolved 1.65 g of4-dimethylaminobenzoic acid followed by the addition of 3.1 g of DCC.After 30 minutes of stirring, 3.36 g of 4-amidino-2-benzoylphenolmethanesulfonate was added to the mixture and the mixture was furtherstirred overnight. The reaction mixture was removed of the insolubles byfiltration and recrystallized from ethanol to yield 1.2 g of4-amidino-2-benzoylphenyl 4-dimethylaminobenzoate methanesulfonate.

EXAMPLE 39

The following compounds were obtained by the procedures similar to thoseof Examples 15 to 25, 29, 31 and 32: ##STR64##

EXAMPLE 40 Synthesis of 4-amidino-2-benzoylphenyl 4-guanidinobenzoate##STR65##

To a solution of 11.6 g of 4-guanidinobenzoic acid hydrochloride in 180ml of dried pyridine, while being cooled in ice, was added 13.2 g ofDCC. After 30 minutes of stirring, 18.0 g of 4-amidino-2-benzoylphenolmethanesulfonate was added, and the mixture was further stirredovernight at room temperature. A white solid substance precipitated fromthe reaction mixture was collected by filtration, washed with acetone,and dissolved in water. The aqueous solution was freed from thewater-insoluble DCU by filtration and added to a saturated aqueoussodium bicarbonate solution, while being cooled in ice and stirred. Theprecipitated pale yellow crystals were collected by filtration, washedwith water, then with acetone, and dried to yield4-amidino-2-benzoylphenyl 4-guanidinobenzoate carbonate.

IR, ν_(max).^(KBr), cm⁻¹ : 3400, 1730 (shoulder), 1700, 1650, 1600.

While cooling in ice, the carbonate was suspended in 6-fold volume ofmethanol and to the suspension was added 2.3-fold moles ofmethanesulfonic acid to turn the suspension into a homogeneous solution.After addition of 40- to 50-fold acetone, triturated to precipitate awhite powder which was recrystallized from aqueous acetone to obtain 7.5g of 4-amidino-2-benzoylphenyl 4-guanidinobenzoate dimethanesulfonate.

EXAMPLE 41 Synthesis of 4-amidino-2-nitrophenyl 4-guanidinobenzoate##STR66##

Into 300 ml of dried pyridine, were dissolved 7.0 g of4-guanidinobenzoyl chloride hydrochloride and 7.4 g of4-amidino-2-nitrophenol methanesulfonate. The solution was stirredovernight at room temperature. The precipitate which was formed wascollected by filtration, suspended in methanol and filtered. Thefiltrate and 300 ml of ethyl ether were stirred to precipitate acolorless solid substance which was collected by filtration, dissolvedin a small volume of methanol, and stirred together with a saturatedsodium bicarbonate solution to precipitate the intended carbonate. Theprecipitated carbonate was collected by filtration, then air-dried,suspended in a small volume of methanol, admixed with methanesulfonicacid at room temperature. After 10 minutes, ethyl ether was added to thereaction mixture to precipitate crystals. The crystals were collected byfiltration, washed thoroughly with ethyl ether to obtain4-amidino-2-nitrophenyl 4-guanidinobenzoate dimethanesulfonate.

mp: 190°-191° C.

IR, ν_(max).^(KBr), cm⁻¹ : 3330, 3200, 1745, 1680, 1560, 1355, 1175.

EXAMPLE 42 Synthesis of 4-amidino-2-(4-guanidinobenzoylamino)phenyl4-guanidinobenzoate ##STR67##

To 50 ml of anhydrous pyridine, was added 4.3 g of 4-guanidinobenzoicacid hydrochloride. To the mixture, while being cooled in ice, was added4.9 g of DCC. After one hour of stirring, 3.4 g of the4-amidino-2-aminophenol dimethanesulfonate obtained in Example 23-b wasadded to the mixture and stirred for 30 minutes while being cooled inice, then overnight at room temperature. After addition of 200 ml ofethyl ether the solvent was removed by decantation. The oily residue wasmixed with 200 ml of water and filtered to remove insolubles. Thefiltrate was mixed with a saturated aqueous sodium bicarbonate solutionand the precipitated crystals were collected by filtration to obtain4-amidino-2-(4-guanidinobenzoylamino)phenyl 4-guanidinobenzoatetricarbonate.

EXAMPLE 43

The following compounds were obtained by the procedures similar to thoseof Examples 40 to 42: ##STR68##

EXAMPLE 44

The following compounds were obtained by the procedures similar to thoseof Examples 15 to 25, 29, 31 and 32: ##STR69##

                                      TABLE 5                                     __________________________________________________________________________    Compound                                                                      No.   Salt                                                                              MP (°C.)                                                                      IR         NMR                                               __________________________________________________________________________    1     MSA 159-161                                                                              3250 3080 1765 1680                                                                      1.93 (3H, s)                                                       1660       2.47 (3H, s)                                                                  7.37-8.33 (8H, m)                                                             9.13-9.70 (4H, br)                                2     MSA 155-158                                                                              3360 3050 3000 1745                                                                      2.38 (3H, s)                                                       1670 1525 1350 1190                                                                      2.45 (3H, s)                                                                  7.77 (1H, d, J = 8.5)                                                         8.27 (1H, d, d, J = 8.5, 2.0)                                                 8.60 (1H, d, J = 2.0)                                                         9.23-9.83 (4H, br)                                3     MSA 173-176                                                                              3250 3100 2940 1755                                                                      1.00 (6H, d, J = 6.5)                                              1675       1.60-2.42 (1H, br-m)                                                          2.45 (3H, s)                                                                  2.45 (2H, d, J = 6.5)                                                         3.87 (3H, s)                                                                  7.17-7.67 (3H, m)                                                             9.05-9.52 (4H, br)                                4     MSA   168-170.5                                                                          3250 3100 2930 1760                                                                      0.63-1.63 (11H, br-m)                                              1670       1.87-2.47 (2H, br-t)                                                          2.42 (3H, s)                                                                  7.30-8.23 (8H, m)                                                             9.07-9.53 (4H, br)                                5     MSA 154-157                                                                              3270 3080 1730 1720                                                                      1.88 (3H, br-d)                                                    1670 1640 1210                                                                           2.47 (3H, s)                                                                  3.82 (3H, s)                                                                  6.13 (1H, d, J = 15.0)                                                        6.45 (2H, m)                                                                  7.25-7.78 (1H, br)                                                            7.57 (1H, d, J = 8.5)                                                         8.17 (1H, d, d, J = 8.5, 2.0)                                                 8.40 (1H, d, J = 2.0)                                                         9.22-9.72 (4H, br)                                6     MSA 139-141                                                                              3550-2850 1720 1655                                                                      1.83 (3H, br-d)                                                    1190       2.47 (3H, s)                                                                  5.77 (1H, d, J = 15.0)                                                        6.25 (2H, m)                                                                  6.87-7.40 (1H, m)                                                             7.47-8.37 (8H, m)                                                             9.20-9.77 (4H, br)                                7     MSA 278.5- 3250 3080 1740 1670                                                                      1.17 (4H, m)                                                280.5  1520 1345 1210                                                                           1.77-2.27 (1H, br-m)                                                          2.47 (3H, s)                                                                  7.73 (1H, d, J = 8.5)                                                         8.25 (1H, d, d, J = 8.5, 2.0)                                                 8.58 (1H, d, J = 2.0)                                                         9.20-9.90 (4H, br)                                8     MSA 158-159                                                                              3250 3060 1745 1665                                                                      0.58-1.02 (4H, m)                                                             1.32-1.82 (1H, br-m)                                                          2.42 (3H, s)                                                                  7.32-8.25 (8H, m)                                                             9.08-9.62 (4H, br)                                9     MSA 205-208                                                                              3280 3130 2920 1750                                                                      1.00-2.93 (11H, br)                                                1675       2.47 (3H, s)                                                                  3.88 (3H, s)                                                                  7.17-7.73 (3H, m)                                                             9.03-9.60 (4H, br)                                10    MSA 138-140                                                                              3270 3070 1755 1675                                                                      2.17-2.60 (2H, br)                                                 1210       2.42 (3H, s)                                                                  2.90-3.37 (2H, br)                                                            5.02 (2H, s)                                                                  7.03-8.27 (14H, m)                                                            9.10-9.67 (4H, br)                                11    2HBr       3600-2400 1760 1670                                                           1655                                                         12    MSA 153-156                                                                              3280 3070 1755 1675                                                                      1.07-1.67 (6H, br)                                                 1215       1.97-2.37 (2H, br)                                                            2.45 (3H, s)                                                                  5.03 (2H, s)                                                                  7.00-8.30 (14H, m)                                                            9.17-9.67 (4H, br)                                13    2HBr                                                                              158-160                                                                              3500-2700 1765 1680                                                                      1.07-1.87 (6H, br)                                                            2.03-2.43 (2H, br)                                                            2.50-3.17 (2H, br)                                                            7.42-8.25 (11H, m)                                                            8.92-9.25 (2H, br)                                                            9.37-9.67 (2H, br)                                14    MSA HCl    1740                                                         15    MSA HCl    1760                                                         16    MSA 156-157                                                                              3300 3100 2900 1745                                                                      0.80-3.10 (12H, br)                                                1680 1190  2.43 (3H, s)                                                                  3.87 (3H, s)                                                                  5.02 (2H, s)                                                                  7.08-7.68 (9H, m)                                                             9.05-9.58 (4H, br)                                17    2HBr                                                                                197-198.5                                                                          3450 3300 3100 2970                                                                      0.82-3.15 (12H, br-m)                                              1750 1675  3.92 (3H, s)                                                                  7.22-8.38 (6H, m)                                                             8.95-9.22 (2H, br)                                                            9.35-9.65 (2H, br)                                18    MSA 158-162                                                                              3320 3100 2900 1740                                                                      0.83-3.13 (12H, br)                                                1725 1675 1200                                                                           2.45 (3H, s)                                                                  3.87 (3H, s)                                                                  5.05 (2H, s)                                                                  7.12-7.48 (1H, br)                                                            7.37 (5H, s)                                                                  7.52 (1H, d, J = 8.5)                                                         8.12 (1H, d, d, J = 8.5, 2.0)                                                 8.35 (1H, d, J = 2.0)                                                         9.08-9.58 (4H, br)                                19    2HBr                                                                              188-189                                                                              3400-2800 1758 1730                                                                      0.80-2.93 (12H, br-m)                                              1670       7.47 (1H, d, J = 8.5)                                                         7.70-8.20 (3H, br)                                                            8.08 (1H, d, d, J = 8.5, 2.0)                                                 8.28 (1H, d, J = 2.0)                                                         8.93-9.20 (2H, br)                                                            9.37-9.60 (2H, br)                                20    MSA 168-170                                                                              3270 3060 1760 1670                                                                      0.60-3.13 (12H, br)                                                1210       2.45 (3H, s)                                                                  5.02 (2H, s)                                                                  6.97-8.30 (14H, m)                                                            9.03-9.73 (4H, br)                                21    2HBr                                                                              156-160                                                                              3500-2600 1750 1680                                                                      0.73-2.90 (12H, br-m)                                              1665       7.40-8.37 (11H, m)                                                            9.03-9.30 (2H, br)                                                            9.43-9.70 (2H, br)                                22    MSA 190-192                                                                              3350 3100 1732 1660                                                                      2.42 (6H, br-s)                                                               7.17-7.97 (6H, m)                                                             7.97-8.37 (2H, m)                                                             9.07-9.57 (4H, br)                                      H.sub.2 CO.sub.3                                                                         3350 2925 2600 1710                                                           1660 1580                                                    23    MSA 203.5-206                                                                            3450-2900 1735 1680                                                                      2.43 (3H, s)                                                       1200       3.88 (3H, s)                                                                  7.43-7.83 (6H, m)                                                             8.00-8.27 (2H, m)                                                             9.07-9.53 (4H, br)                                24    MSA ˜153(d)                                                                        3340 3150 2750 1720                                                                      2.52 (3H, s)                                                       1690       7.33-8.57 (8H, m)                                                             9.07-9.43 (4H, br)                                25    MSA 191-192                                                                              3340 3130 1730 1685                                                                      2.45 (3H, s)                                                       1215       3.73 (3H, s)                                                                  7.65- 7.98 (4H, m)                                                            8.12-8.42 (3H, m)                                                             8.53 (1H, d, J = 2.0)                                                         9.22-9.85 (4H, br)                                26    MSA 203-205                                                                              3350 3080 1643 1625                                                                      2.50 (3H, s)                                                                  7.47-8.40 (8H, m)                                                             9.17-9.78 (4H, br)                                27    MSA 232-235                                                                              3450 3350 3050 1715                                                                      2.47 (3H, s)                                                       1615 1540 1350 1215                                                                      7.60-8.48 (7H, m)                                                             8.70 (1H, d, J = 2.0)                                                         9.24-9.85 (4H, br)                                28        >300   3400-3000 1745 1685                                                           1235                                                         29    MSA ˜160                                                                           3275 3100 1730 1675                                                                      2.48 (3H, s)                                                       1650       7.25-8.38 (13H, m)                                                            9.17-9.76 (4H, br)                                30    MSA 233-234                                                                              3400-2800 1738 1660                                                                      2.48 (3H, s)                                                       1220       7.33-8.26 (13H, m)                                                            8.96-9.53 (4H, br)                                                            10.36 (1H, s)                                     31    MSA 205˜                                                                           3270 3080 1725 1660                                                                      2.50 (3H, s)                                                       1635 1210  3.93 (3H, s)                                                                  6.90 (1H, d, J =  16.0)                                                       7.33-8.13 (9H, m)                                                             9.13-9.60 (4H, br)                                32    MSA 158-160                                                                              3360 3140 1770 1710                                                                      2.40 (3H, s)                                                       1680 1495 1210                                                                           2.95 (4H, s)                                                                  3.82 (3H, s)                                                                  7.27 (7H, br-s)                                                               7.53 (1H, s)                                                                  8.97-9.43 (4H, br)                                33    MSA 173-175                                                                              3250 3095 1765 1690                                                                      1.33-2.67 (6H, m)                                                  1685 1220 1110                                                                           2.38 (3H, s)                                                                  7.00-8.27 (13H, br)                                                           9.07-9.60 (4H, br)                                34    MSA 176-180                                                                              3500-2800 1745 1665                                                           1220 1180                                                    35    MSA 185-189                                                                              3300 3120 1730 1680                                                           1205                                                         36    MSA 93-95  3250 3030 1720                                                     H.sub.2 SO.sub.4                                                                  100-103                                                                              3700-2600 1750 1690                                                                      2.43 (3H, s)                                                                  8.42-10.68 (m)                                    37    MSA 220-222                                                                              3400-2900 1750 1690                                                                      2.50 (6H, s)                                                       1250-1150  7.50 (2H, d, J = 8.0)                                                         7.97 (1H, d, J = 8.0)                                                         8.12 (2H, d, J =  8.0)                                                        8.42 (1H, d, d, J = 5.0, 2.0)                                                 8.75 (1H, d, J = 2.0)                                                         9.37-9.95 (4H, br)                                38    MSA 179-180                                                                              3090 2950 1735 1680                                                           1608 1350 1230 1180                                          39    MSA 187-188                                                                              3400-2950 1740 1670                                                                      1.27 (9H, s)                                                       1210 1180  2.50 (3H, s)                                                                  7.20-8.43 (12H, m)                                                            9.10-10.00 (4H, br)                               40    MSA 134-136                                                                              3500-2900 1765 1675                                                                      0.86 (6H, d, J = 6.0)                                              1210       1.23 (3H, d, J = 7.0)                                                         2.45 (3H, s)                                                                  7.00-8.17 (12H, m)                                                            8.87-9.53 (4H, br)                                41    MSA 104-107                                                                              3450-2650 1741 1613                                                                      2.45 (3H, s)                                                       1200       3.73 (3H, s)                                                                  8.43-9.90 (12H, m)                                                            9.13-9.63 (4H, br)                                42    MSA 192-194                                                                              3300 3100 1740 1685                                                                      2.47 (3H, s)                                                       1660 1205 1170                                                                           3.80 (3H, s)                                                                  6.95 (2H, d, J = 9.0)                                                         7.23-8.50 (10H, m)                                                            8.75-9.72 (4H, br)                                43    MSA 153-154                                                                              3270 3100 1765 1685                                                                      2.40 (3H, s)                                                       1490 1220  3.75 (3H, s)                                                                  3.83 (3H, s)                                                                  3.97 (2H, s)                                                                  6.70-7.60 (7H, m)                                                             8.98-9.45 (4H, br)                                44    MSA 181-183                                                                              3600-2750 1730 1680                                                                      0.70-2.05 (7H, m)                                                  1280-1140  2.50 (3H, s)                                                                  4.13 (2H, q, J = 6.0)                                                         7.16 (2H, d, J = 9.0)                                                         7.73-8.58 (4H, m)                                                             8.72 (1H, d, J = 2.0)                                                         9.22-10.02 (4H, br)                               45    MSA 132-134                                                                              3300 3100 1750 1670                                                                      2.47 (3H, s)                                                       1600 1460 1445 1250                                                                      5.20 (2H, s)                                                                  6.97-8.60 (17H, br)                                                           9.40-10.13 (4H, br)                               46    HBr 202-204                                                                              3300 3100 1715 1660                                                                      6.80 (2H, d, J = 8.0)                                              1605 1275 1210                                                                           7.27-8.47 (10H, m)                                                            8.70-9.80 (5H, br)                                47    MSA 255-258                                                                              3600-2750 1740 1690                                                                      2.47 (3H, s)                                                       1440       6.25 (2H, s)                                                                  7.18 (1H, d, J = 8.0)                                                         7.62 (1H, d, J = 1.5)                                                         7.87 (1H, d, d, J = 8.0, 1.5)                                                 8.28 (2H, s)                                                                  9.23-9.72 (4H, br)                                48    MSA 176-179                                                                              3300 3100 1725 1690                                                                      2.53 (3H, s)                                                       1620 1530 1450 1350                                                                      6.10 (2H, s)                                                       1230       6.47-8.70 (11H, m)                                                            9.20-10.03 (4H, br)                               49    MSA 200-202                                                                              3270 3100 1725 1660                                                                      2.43 (3H, s)                                                       1588 1173  2.47 (3H, s)                                                                  7.18-8.28 (12H, m)                                                            9.18-9.65 (4H, br)                                50    MSA 175-177                                                                              3400-2900 1750 1720                                                                      2.43 (3H, s)                                                       1700 1665 1210                                                                           7.20-8.48 (12H, m)                                                            9.03-9.90 (4H, br)                                51    MSA 165-170                                                                              3600-2900 1750 1730                                                                      2.45 (3H, s)                                                       1690 1200  3.75 (3H, s)                                                                  7.75 (2H, d, J = 8.0)                                                         7.95-8.62 (5H, m)                                                             9.12-9.95 (4H, br)                                                            10.17 (1H, s)                                     52    MSA 164-165                                                                              3250 3050 1755 1705                                                                      2.43 (3H, s)                                                       1670 1210  7.33-8.30 (12H, br)                                                           9.07-9.60 (4H, br)                                                            10.00 (1H, s)                                     53    P--TsOH                                                                           100-106                                                                              3500-2900 1740 1660                                                           1210                                                         54    MSA 144-146                                                                              3350 3050 1765 1725                                                                      2.30 (3H, s)                                                       1665 1625 1475 1310                                                                      2.50 (3H, s)                                                                  6.53 (1H, d, J = 16.0)                                                        7.17-8.30 (13H, br)                                                           (4H, br)                                          55    MSA 167-169                                                                              3500 3200 1760 1740                                                                      2.27 (3H, s)                                                       1690 1670 1480 1310                                                                      2.43 (3H, s)                                                                  2.37-2.73 (4H, m)                                                             6.93-8.27 (12H, m)                                                            9.14-9.81 (4H, br)                                56    MSA 241-243                                                                              3260 3050 1740 1680                                                                      2.10 (3H, s)                                                       1600 1205 1180                                                                           2.43 (3H, s)                                                                  7.63 (br-s)                                                                   8.10 (1H, s)                                                                  9.10- 9.67 (4H, br)                                                           10.37 (1H, s)                                     57    MSA 157-159                                                                              3300 1735 1670 1540                                                                      2.43 (3H, s)                                                       1495 1255 1200                                                                           3.87 (3H, s)                                                                  4.33 (2H, d, J = 5.0)                                                         5.03 (2H, s)                                                                  7.30-8.10 (12H, br)                                                           8.93-9.53 (4H, br)                                58    2HBr                                                                              229-231                                                                              3250 3100 1745 1665                                                                      3.93 (3H, s)                                                       1590 1480 1255 1230                                                                      4.23 (2H, J = 5.0)                                                            7.57-8.27 (5H, m)                                                             8.34-8.81 (2H, br)                                                            8.94-9.67 (4H, br)                                59    MSA 137-139                                                                              3300 3100 1730 1680                                                           1540 1310 1255                                               60    2HBr                                                                              204-206                                                                              3550 3200 1750 1730                                                                      3.43 (3H, s)                                                       1670 1480 1430 1260                                                                      3.73 (3H, s)                                                       1220       6.35 (2H, d, J = 5.0)                                                         7.67-8.80 (9H, m)                                                             9.03-9.93 (4H, br)                                61    MSA 150-152                                                                              3350 3100 1745 1680                                                                      2.47 (3H, s)                                                       1530 1350 1260 1230                                                                      4.37 (2H, d, J = 5.0)                                                         5.07 (2H, s)                                                                  7.33-8.66 (12H, br)                                                           9.19-9.89 (4H, br)                                62    2HBr                                                                              215-218                                                                              3050 1760 1670 1540                                                           1355 1220                                                    63    MSA 102-104                                                                              3250 3050 1740 1610                                                           1470 1445 1315 1260                                          64    2HBr       3300 3100 1745 1670                                                           1640 1470 1320 1220                                          65    2MSA                                                                              165-168                                                                              3500-2600 1760 1705                                                                      1.63-3.15 (6H, m)                                                  1690 1210  2.50 (3H, s)                                                                  3.93 (3H, s)                                                                  7.20-7.93 (9H, m)                                                             9.02-9.77 (4H, br)                                66    MSA   190-194(d)                                                                         3250 3080 1730 1665                                                                      2.40 (3H, s)                                                       1602 1165  2.94 (6H, s)                                                                  6.55 (2H, d, J = 8.0)                                                         7.33-8.27 (10H, m)                                                            9.00-9.57 (4H, br)                                67    MSA 181-187                                                                              3550-2900 1730 1660                                                                      2.43 (3H, s)                                                       1200       7.23-8.50 (14H, m)                                                            9.03-9.83 (4H, br)                                68    MSA 183-187                                                                              3500-2800 1760 1710                                                           1220 1160                                                    69    H.sub.2 CO.sub.3                                                                         3400 1730 1700 1650                                                           1600                                                               2MSA                                                                              220-224                                                                              3500-2900 1740 1655                                                                      2.47 (6H, s)                                                       1605 1210 1185 1040                                                                      7.27-8.37 (16H, m)                                                            9.12-9.62 (4H, br)                                                            10.23 (br-s)                                      70    2MSA                                                                              190-191                                                                              3330 3200 1745 1680                                                           1560 1355 1175                                               71    2MSA                                                                              218-220                                                                              3300 3150 1730 1675                                                                      2.50 (6H, s)                                                       1265 1210 1180                                                                           3.90 (3H, s)                                                                  7.27-8.33 (11H, m)                                                            9.07-9.60 (4H, br)                                                            10.28 (1H, br-s)                                  72    MSA HCl                                                                           141(d) 3650-2500 1745 1720                                                                      2.52 (3H, s)                                                       1680 1600 1265 1230                                                                      3.78 (3H, s)                                                       1185       7.33-8.58 (11H, m)                                                            9.32-9.95 (4H, br)                                                            10.82 (1H, br)                                    73    3H.sub.2 CO.sub.3                                                                 85˜(d)                                                                         3700-2400 1720 1660                                                           1605                                                         74    2MSA       3300 3100 1720 1660                                                           1200                                                         75    2MSA                                                                              222-227                                                                              3500-3000 1740 1690                                                                      2.37 (3H, s)                                                       1210 1170  2.50 (6H, s)                                                                  3.92 (3H, s)                                                                  7.20-8.43 (10H, m)                                                            9.02-9.62 (4H, br)                                                            9.78 (1H, br)                                     76    2-PTsOH    3550-2850 1750 1680                                                           1190                                                         77    2-PTsOH                                                                           120˜(d)                                                                        3500-2900 1750 1670                                                           1200                                                         78    MSA HCl                                                                             101-102(d)                                                                         3300 3150 1715 1670                                                           1585 1190                                                    79    MSA   83-84(d)                                                                           3250 3050 1740 1665                                                           1205                                                         80    MSA 204-207                                                                              3300 3100 1755 1680                                                                      2.45 (3H, s)                                                       1205 1170  2.60 (3H, s)                                                                  3.92 (3H, s)                                                                  7.57 (1H, s)                                                                  7.63 (2H, d, J = 7.0)                                                         8.17 (1H, s)                                                                  8.22 (2H, d, J = 6.0)                                                         9.02-9.75 (4H, br)                                81    MSA 178-180                                                                              3400-2900 1750 1670                                                                      2.50 (3H, s)                                                       1220 1210  7.27-8.57 (11H, m)                                                            9.05-9.97 (4H, br)                                82    MSA 136-137                                                                              3450-3000 1765 1690                                                                      1.67-3.20 (6H, m)                                                  1210       2.47 (3H, s)                                                                  3.88 (3H, s)                                                                  7.27-7.73 (5H, m)                                                             8.17 (2H, d, J = 8.0)                                                         8.98-9.75 (4H, br)                                83    MSA 183-186                                                                              3500-3000 2250 1760                                                                      2.47 (3H, s)                                                       1740 1675 1220                                                                           7.30-8.55 (12H, m)                                                            9.15-9.85 (4H, br)                                84    MSA 186-188                                                                              3600-2900 1740 1730                                                                      2.52 (3H, s)                                                       1680 1220  3.78 (3H, s)                                                                  7.27-8.75 (7H, m)                                                             9.25-9.95 (4H, br)                                85    MSA 123-125                                                                              3400 3100 1750 1690                                                                      2.47 (3H, s)                                                       1200       7.23-8.40 (7H, m)                                                             8.58-9.07 (4H, br)                                86    MSA 143-144                                                                              3400-2800 1750 1660                                                                      1.25 (3H, d, J = 7.0                                               1200       2.45 (3H, s)                                                                  6.98-8.18 (12H, m)                                                            8.88-9.51 (4H, br)                                87    MSA 210-212                                                                              3330 3050 1690 1670                                                           1570 1500 1315 1270                                          __________________________________________________________________________

What is claimed is:
 1. An amidino compound or a pharmaceuticallyacceptable acid addition salt thereof, said amidino compound beingrepresented by the formula ##STR70## wherein R₁ represents a straight orbranched chain alkyl group of 1 to 6 carbon atoms, a straight orbranched chain alkenyl group of 2 to 6 carbon atoms including 1 to 3double bonds, R₃ --(CH₂)_(a) --, R₄ (CH₂)_(b) --, ##STR71## where R₃ iscycloalkyl group of 3 to 6 carbon atoms or cycloalkenyl group of 3 to 6carbon atoms including 1 to 2 double bonds; a is 0, 1, 2 or 3; R₄ isamino or guanidino group possessing radical protecting group or not; bis a number of 1 to 5; R₅ and R₆, which may be the same or different,are each a hydrogen atom, straight or branched alkyl group of 1 to 4carbon atoms, --OR₇, methylenedioxy group, --SR₇, --COOR₇, --COR₈,--OCOR₉, --NHCOR₉, ##STR72## NO₂, CN, halogen atom, --CF₃ or ##STR73##R₇ is hydrogen atom, straight or branched alkyl group of 1 to 4 carbonatoms or benzyl group; R₈ is hydrogen atom, straight or branched alkylgroup of 1 to 4 carbon atoms; R₉ is straight or branched alkyl group of1 to 4 carbon atoms; R₁₀ and R₁₁, which may be the same or different,are each a hydrogen atom, straight or branched alkyl group of 1 to 4carbon atoms, or amino radical protecting group R₁₂ is O, S or NH; R₁₃is 2',3'-dimethyl or 3'-CF₃ group; Z is --(CH₂)_(d) --(d is 0, 1, 2 or3), ##STR74## R₁₄ is straight or branched alkyl group of 1 to 4 carbonatoms; R₁₅ is hydrogen atom, straight or branched alkyl group of 1 to 4carbon atoms; R₂ represents --OR₁₆, NO₂ or ##STR75## wherein R₁₆ isstraight or branched alkyl group of 1 to 4 carbon atoms; wherein saidprotecting group is an amino or guanidino radical protecting groupselected from the group consisting of t-butoxycarbonyl,benzyloxycarbonyl, acetyl, benzoyl, tosyl, nitro, benzyl and t-butylgroups.
 2. An amidino compound which is 4-amidino-2-benzoylphenyl4-guanidino benzoate, and a pharmaceutically acceptable acid additionsalt thereof.
 3. An amidino compound or a pharmaceutically acceptableacid addition salt thereof according to claim 1, wherein R₂ is 2--OR₁₆,2--NO₂ or ##STR76##
 4. An amidino compound or a pharmaceuticallyacceptable acid addition salt thereof according to claim 1, wherein R₂is 2--OCH₃, 2--NO₂ or ##STR77##
 5. An anticomplement agent comprising asan active ingredient an amidino compound or a pharmaceuticallyacceptable acid addition salt thereof according to claim
 1. 6. Ananticomplement agent comprising as an active ingredient an amidinocompound or a pharmaceutically acceptable acid addition salt thereofaccording to claim
 3. 7. An anticomplement agent comprising as an activeingredient an amidino compound or a pharmaceutically acceptable acidaddition salt thereof according to claim 4.